Piperidinyl compounds as NK1 or NK2 antagonists

ABSTRACT

Compounds of formula I ##STR1## wherein Q 1 , Q 2 , Q 3 , Q 4 , and Q 5  have any of the meanings given in the specification, their N-oxides, and their pharmaceutically acceptable salts are nonpeptide antagonists of SP and NKA are useful for the treatment of asthma, etc. Also disclosed are pharmaceutical compositions, processes for preparing the compounds of formula I and intermediates.

This is a divisional of U.S. application Ser. No. 08/547,512 filed onOct. 24, 1995 now U.S. Pat. No. 5,710,169.

This invention concerns novel substituted 1,2-ethanediamine derivativeswhich antagonize the pharmacological actions of the endogenousneuropeptide tachykinins known as neurokinins, particularly at theneurokinin 1 (NK1) and the neurokinin 2 (NK2) receptors. The novel1,2-ethanediamine derivatives are useful whenever such antagonism isdesired. Thus, such compounds may be of value in the treatment of thosediseases in which the NK1 and/or NK2 receptor is implicated, forexample, in the treatment of asthma and related conditions. Theinvention also provides pharmaceutical compositions containing the novel1,2-ethanediamine derivatives for use in such treatment, methods fortheir use, and processes and intermediates for the manufacture of thenovel 1,2-ethanediamine derivatives.

The mammalian neurokinins comprise a class of peptide neurotransmitterswhich are found in the peripheral and central nervous systems. The threeprincipal neurokinins are SP (SP), Neurokinin A (NKA) and Neurokinin B(NKB). There are also N-terminally extended forms of at least NKA. Atleast three receptor types are known for the three principalneurokinins. Based upon their relative selectivities favoring theneurokinin agonists SP, NKA and NKB, the receptors are classifed asneurokinin 1 (NK1), neurokinin 2 (NK2) and neurokinin 3 (NK3) receptors,respectively. In the periphery, SP and NKA are localized in C-afferentsensory neurons, which neurons are characterized by non-myelinated nerveendings known as C-fibers, and are released by selective depolarizationof these neurons, or selective stimulation of the C-fibers. C-Fibers arelocated in the airway epithelium, and the tachykinins are known to causeprofound effects which clearly parallel many of the symptoms observed inasthmatics. The effects of release or introduction of tachykinins inmammalian airways include bronchoconstriction, increased microvascularpermeability, vasodilation, increased mucas secretion, neurogenicinflamation and activation of mast cells. Thus, the tachykinins areimplicated in the pathophysiology and airway hyperresponsivenessobserved in asthmatics; and blockade of the action of releasedtachykinins may be useful in the treatment of asthma and relatedconditions. A cyclopeptide antagonists (FK-224) selective for both NK1and NK2 receptors has demonstrated clinical efficacy in human patientssuffering from asthma and chronic bronchitis. M. Ichinose, et al.,Lancet, 1992, 340, 1248. Nonpeptidic tachykinin antagonists have beenreported, for example in European Patent Application, Publication Number(EPA) 428434, EPA 474561, EPA 512901, EPA 512902, EPA 515240 and EPA559538, as well as in WO 94/10146.

K. Nagarajan, et al., Proc. Indian Acad. Sci. (Chem. Sci.), 1992, 104,383-397 (Nagarajan), discloses the synthesis of 1,2-ethanediaminederivatives of formula I (formula set out hereinbelow following theExamples, together with other formulae denoted by Roman numerals)wherein Q¹ is a pyrrolidino or piperidino radical of formula Id and Q⁴is phenyl, 3,4-dimethoxyphenyl, 3,4-(methylenedioxy)phenyl,3-methoxyphenyl, or 2-thienyl. The compounds disclosed in Nagarajan havebeen excluded from the definition of the compounds of the inventionhereinbelow. Nagarajan does not disclose pharmaceutical compositionscontaining the compounds disclosed therein, nor does Nagarajan disclosea pharmaceutical utility for the compounds.

We have discovered a series of non-peptidic antagonists of the NK1 andNK2 receptors, and this is the basis for our invention.

According to the invention, there is provided a Compound of theinvention which is a compound of formula I, wherein

Q¹ is a radical selected from the group of radicals of formulae Ia, Ib,Ic, Id, Ie, If, Ig, Ih, Ij, Ik and Im, wherein

for a radical of formula Ia, Z^(a) is nitrogen or a group CR^(ad) inwhich R^(ad) is hydrogen or R^(ad) together with R^(ac) and the existingcarbon to carbon bond forms a double bond; R^(aa) is Ar or Het; R^(ab)is hydrogen and R^(ac) is hydrogen or hydroxy or R^(ac) together withR^(ad) and the existing carbon to carbon bond forms a double bond, orR^(ac) and R^(ad) together form a diradical --(CH₂)_(j) -- in which j isan integer from 1 to 5; or R^(ab) and R^(ac) together form a diradical--(CH₂)_(k) -- in which k is an integer from 2 to 6, or R^(ab) andR^(ac) together are oxo or dialkylaminoalkyloxyimino of formula═N--O--(CH₂)_(q) --NR^(ae) R^(af) in which q is the integer 2 or 3 andR^(ae) and R^(af) are independently hydrogen or (1-4C)alkyl, or theradical NR^(ae) R^(af) is pyrrolidino, piperidino or morpholino;

for a radical of formula Ib, Z^(b) is a substituted imino group R^(ba) Nor R^(ba) CH₂ N in which R^(ba) is (3-7C)cycloakyl, Ar or Het; or Z^(b)is a disubstituted methylene group R^(bb) (CH₂)_(p) --C--R^(bc) in whichR^(bb) is Ar or Het; p is the integer 0 or 1; and R^(bc) is hydrogen,hydroxy, (1-4C)alkoxy, (1-4C)alkanoyloxy, COOR^(bd) (wherein R^(bd) ishydrogen or (1-3C)alkyl), cyano, NR^(be) R^(bf) or SR^(bg) in whichR^(be) and R^(bf) are independently hydrogen, (1-4C)alkyl,(1-4C)hydroxyalkyl or (1-4C)alkanoyl, or the radical NR^(be) R^(bf) ispyrrolidino, piperidino or morpholino; and R^(bg) is hydrogen or(1-4C)alkyl; or R^(bc) forms a double bond with the carbon atom to whichit is bonded and with the adjacent carbon atom in the piperidine ring;or Z^(b) is a disubstituted methylene group R^(bh) CR^(bi) which forms aspirocyclic ring wherein R^(bh) is phenyl which is joined by anortho-substituent diradical X^(b) to R^(bi) in which the phenyl R^(bh)may bear a further substituent selected from halo, (1-3C)alkyl,(1-3C)alkoxy, hydroxy, (1-3C)alkylthio, (1-3C)alkylsulfinyl and(1-3C)alkylsulfonyl; the diradical X^(b) is methylene, carbonyl orsulfonyl; and R^(bi) is oxy or imino of formula --NR^(bj) -- in whichR^(bj) is hydrogen or (1-3C)alkyl;

for a radical of formula Ic, R^(ca) is Ar or Het; and Z^(c) is oxo,thio, sulfinyl, sulfonyl or imino of formula --NR^(cb) -- in whichR^(cb) is (1-3C)alkyl or R^(cc) R^(cd) N--(CH₂)_(q) -- in which q is theinteger 2 or 3 and in which R^(cc) and R^(cd) are independently hydrogenor (1-3C)alkyl or the radical R^(cc) R^(cd) N is pyrrolidino, piperidinoor morpholino;

for a radical of formula Id, R^(da) is 1, 2 or 3;

for a radical of formula Ie, J^(e) is oxygen, sulfur or NR^(ea) in whichR^(ea) is hydrogen or (1-3C)alkyl; R^(eb) is hydrogen, (1-6C)alkyl whichmay bear a hydroxy substituent and/or one to three fluoro substituents,(3-6C)alkenyl (in which a vinyl carbon is not bound to nitrogen),2-hydroxyethyl, (3-7C)cyloalkyl, Ar or Het; R^(ec) is hydrogen,(1-6C)alkyl which may bear a hydroxy substituent and/or one to threefluoro substituents, (3-6C)cycloalkyl, (1-5C)alkoxy (only when J^(e) isoxygen), (3-6C)cycloalkoxy (only when J^(e) is oxygen), or an aminogroup of formula NR^(ed) R^(ee) containing zero to seven carbon atoms inwhich each of R^(ed) and R^(ee) is independently hydrogen, (1-5C)alkylor (3-6C)cycloalkyl, or the radical NR^(ed) R^(ee) is pyrrolidino,piperidino, morpholino, thiomorpholino (or its S-oxide) or piperazinyl(which piperazinyl group may bear a (1-3C)alkyl substituent at the4-position);

for a radical of formula If, J^(f) is oxygen, sulfur or NR^(fa) in whichR^(fa) is hydrogen or (1-3C)alkyl; L^(f) is a divalent hydrocarbon groupin which the 1-position is bound to the carbon bearing the group J^(f),the divalent group L^(f) being selected from trimethylene,cis-propenylene, tetramethylene, cis-butenylene, cis-but-3-enylene,cis,cis-butadienylene, pentamethylene and cis-pentenylene which divalentgroup L^(f) itself may bear one or two methyl substituents;

for a radical of formula Ig, Z^(g) is (1-8C)alkyl or (3-8C)cycloalkylwhich may bear one or more substituents selected from the groupconsisting of halo, (3-6C)cycloalkyl, cyano, nitro, hydroxy,(1-4C)alkoxy, (1-5C)alkanoyloxy, aroyl, heteroaroyl, oxo, imino (whichmay bear a (1-6C)alkyl, (3-6C)cycloalkyl, (1-5C)alkanoyl or aroylsubstituent), hydroxyimino (which hydroxyimino may bear a (1-4C)alkyl ora phenyl substituent on the oxygen), an amino group of formula NR^(ga)R^(gb), an amino group of formula NR^(gc) R^(gd), an amidino group offormula C(═NR^(gg))NR^(ge) R^(gf), and a carbamoyl group of formulaCON(OR^(gh))R^(gi), but excluding any radical wherein a hydroxy and anoxo substituent together form a carboxy group, wherein an amino group offormula NR^(ga) R^(gb) contains zero to seven carbon atoms and each ofR^(ga) and R^(gb) is independently hydrogen, (1-5C)alkyl or(3-6C)cycloalkyl, or the radical NR^(ga) R^(gb) is pyrrolidino,piperidino, morpholino, thiomorpholino (or its S-oxide) or piperazinyl(which piperazinyl may bear a (1-3C)alkyl substituent group at the4-position); and wherein R^(gc) is hydrogen or (1-3C)alkyl and R^(gd) is(1-5C)alkanoyl, aroyl or heteroaroyl; or R^(gd) is a group of formulaC(═J^(g))NR^(ge) R^(gf) in which J^(g) is oxygen, sulfur, NR^(gg) orCHR^(gj) ; and wherein the amino group NR^(ge) R^(gf) contains zero toseven carbon atoms and each of R^(ge) and R^(gf) is independentlyhydrogen, (1-5C)alkyl or (3-6C)cycloalkyl, or the radical NR^(ge) R^(gf)is pyrrolidino, piperidino, morpholino, thiomorpholino (or its S-oxide)or piperazinyl (which piperazinyl may bear a (1-3C)alkyl substituent atthe 4-position) or R^(ge) is hydrogen or (1-4C)alkyl and R^(gf) togetherwith R^(gg) forms an ethylene or trimethylene group; R^(gg) is hydrogen,(1-4C)alkyl or together with R^(gf) forms an ethylene or trimethylenegroup; R^(gj) is cyano, nitro or SO₂ R^(gk) and R^(gk) is (1-4C)alkyl orphenyl; R^(gh) and R^(gi) are independently (1-3C)alkyl; and in which acyclic group which is a substituent on Z^(g) or formed by substitutionon Z^(g) may bear one or more (1-3C)alkyl groups on carbon as furthersubstituents; and in which any aryl or heteroaryl group which is a partof the group Z^(g) may bear one or more halo, (1-4C)alkyl, (1-4C)alkoxy,cyano, trifluoromethyl or nitro substituents;

for a radical of formula Ih, G^(h) denotes a single bond, a double bondor a divalent hydrocarbon radical; J^(h) denotes a radical joined to thering by a single bond if G^(h) denotes a double bond or, otherwise, aradical joined by a double bond; M^(h) denotes a heteroatom, asubstituted heteroatom, or a single bond; and L^(h) denotes ahydrocarbon radical in which the 1-position is attached to M^(h) ;wherein the values of G^(h), J^(h), M^(h) and L^(h) are selected from

(a) G^(h) is a single bond; J^(h) is oxo or thioxo; M^(h) is oxy, thioor NR^(ha) ; and L^(h) is L^(ha) ;

(b) G^(h) is a single bond; J^(h) is NR^(hb) ; M^(h) is NR^(ha) ; andL^(h) is L^(ha) ;

(c) G^(h) is a double bond, J^(h) is OR^(ha), SR^(ha) or NR^(hc) R^(hd); M^(h) is nitrogen; and L^(h) is L^(ha) ;

(d) G^(h) is methylene which may bear one or two methyl substituents;J^(h) is oxo, thioxo or NR^(he) ; M^(h) is oxy, thio, sulfinyl, sulfonylor NR^(ha) ; and L^(h) is L^(hb) ;

(e) G^(h) is a single bond; J^(h) is oxo, thioxo or NR^(he) ; M^(h) isnitrogen; and L^(h) is L^(hc) ;

(f) G^(h) is methine, which may bear a (1-3C)alkyl substituent; J^(h) isoxo, thioxo or NR^(he) ; M^(h) is nitrogen; and L^(h) is L^(hd) ;

(g) G^(h) is cis-vinylene, which may bear one or two methylsubstituents; J^(h) is oxo, thioxo, or NR^(he) ; M^(h) is nitrogen; andL^(h) is L^(he) ; and

(h) G^(h) is a single bond; J^(h) is oxo or thioxo; M^(h) is a singlebond; and L^(h) is L^(hf) ; wherein

R^(ha) is hydrogen or (1-3C)alkyl; R^(hb) is hydrogen, (1-3C)alkyl,cyano, (1-3C)alkylsulfonyl or nitro; R^(hc) and R^(hd) are independentlyhydrogen or (1-3C)alkyl or the radical NR^(hc) R^(hd) is pyrrolidino,piperidino, morpholino, thiomorpholino (or its S-oxide) or piperazinyl(which piperazinyl may bear a (1-3C)alkyl substituent at the4-position); R^(he) is hydrogen or (1-3C)alkyl; L^(ha) is ethylene,cis-vinylene, trimethylene or tetramethylene which radical L^(ha) itselfmay bear one or two methyl substituents; L^(hb) is ethylene ortrimethylene which radical L^(hb) itself may bear one or two methylsubstituents; L^(hc) is prop-2-en-1-yliden-3-yl, which radical L^(hc)itself may bear one or two methyl substituents; L^(hd) is cis-vinylene,which radical L^(hd) itself may bear one or two methyl substituents;L^(he) is methine, which radical L^(he) itself may bear a (1-3C)alkylsubstituent; and L^(hf) is 4-oxabutan-1,4-diyl;

for a radical of formula Ij, X^(j) is (1-6C)alkyl, --CH₂ OR^(ja), --CH₂SR^(ja), --CH₂ S (O)R^(jg), --CH₂ S(O)₂ R^(jg), --COR_(ja), --COOR^(ja),--C(═J^(ja))NR^(jb) R^(jc), --C(R^(ja))(OR^(jd))(OR^(je)), --CH₂N(R^(ja))C(═J^(ja))R^(jf), --CH₂ N(R^(ja))COOR^(jg) or --CH₂N(R^(ja))C(═J^(ja))NR^(jb) R^(jc) ; B^(j) is a direct bond and L^(j) isa hydrocarbon chain in which the 1-position is bound to B^(j) and L^(j)is selected from trimethylene, tetramethylene, cis-1-butenylene andcis,cis-butadienylene; or B^(j) is N(R^(jh)) and L^(j) is a hydrocarbonchain selected from ethylene, trimethylene and cis-vinylene; or B^(j) isN and L^(j) is a hydrocarbon chain in which the 1-position is bound toB^(j) and L^(j) is cis,cis-prop-2-en-1-ylidin-3-yl; J^(j) and J^(ja) areindependently oxygen or sulfur; R^(ja), R^(jf) and R^(jh) areindependently hydrogen or (1-6C)alkyl; R^(jb) and R^(jc) areindependently hydrogen or (1-6C)alkyl; or the radical NR^(jb) R^(jc) ispyrrolidino, piperidino, morpholino, thiomorpholino (or its S-oxide) orpiperazinyl (which piperazinyl may bear a (1-3C)alkyl substituent at the4-position); R^(jd) and R^(je) are independently (1-3C)alkyl or togetherform a divalent hydrocarbon chain selected from ethylene andtrimethylene; R^(jg) is (1-6C)alkyl; and

for a radical of formula Ik, Z^(k) is a nitrogen linked radical offormula II wherein E¹, E², E³ and E⁴ form a divalent four membered chain(--E¹ =E² --E³ =E⁴ --) in which each of E¹, E², E³ and E⁴ is methine; orin which one or two of E¹, E², E³ and E⁴ is nitrogen and the remainingE¹, E², E³ and E⁴ are methine; and further wherein one or more of E¹,E², E³ and E⁴ which is methine may bear a halo, (1-3C)alkyl, hydroxy,(1-3C)alkoxy, (1-3C)alkylthio, (1-3C)alkylsulfinyl or(1-3C)alkylsulfonyl substituent; and wherein the radicals F^(k), G^(k),and I^(k) (X^(k)) are selected from

(a) G^(k) is a direct bond, I^(k) (X^(k)) is a radical having theformula ═C(Z^(k))-- and F^(k) is a radical selected from --CH═ and --N═;

(b) G^(k) is a direct bond, I^(k) (X^(k)) is a radical having theformula --C(═J^(k))-- and F^(k) is a radical selected from--N(R^(kf))--, --CH₂ --CH₂ --, --CH═CH--, --CH₂ --N(R^(kf))-- and--CH═N--;

(c) G^(k) is a radical having the formula --CH₂ --, I^(k) (X^(k)) is aradical having formula --C(═J^(k))-- and F^(k) is selected from --CH₂ --and --N(R^(kf))--; and

(d) G^(k) is selected from --CH₂ --, --CH₂ --CH₂ --, --CH═CH-- and--N═CH--, I^(k) (X^(k)) is a radical having the formula --C(═J^(k))--and F^(k) is a direct bond; wherein

J^(k) is oxygen or sulfur; Z^(k) is --OR^(ka), --SR^(ka), --COR^(ka),--COOR^(ka), --C(═J^(ka))NR^(kb) R^(kc) or --C(R^(ka)) (OR^(kd))(OR^(ke)); J^(ka) is oxygen or sulfur; R^(ka) and R^(kf) areindependently hydrogen or (1-6C)alkyl; R^(kb) and R^(kc) areindependently hydrogen or (1-6C)alkyl; or the radical NR^(kb) R^(kc) ispyrrolidino, piperidino, morpholino, thiomorpholino (or its S-oxide) orpiperazinyl (which piperazinyl may bear a (1-3C)alkyl substituent at the4-position); R^(kd) and R^(ke) are independently (1-3C)alkyl or R^(kd)and R^(ke) together form ethylene or trimethylene; or Z^(k) is an imidoradical selected from phthalimido, succinimido, maleimido, glutarimido,and 3-oxa-, 3-thia- and 3-azaglutarimido, in which the imido radical maybear one or more (1-3C)alkyl substituents and, in addition, the aromaticportion of the phthalimido may bear one or more halo, hydroxy or(1-3C)alkoxy substituents;

for a radical of formula Im, R^(ma) is 1 or 2; and wherein

for a radical Q¹, Ar is a phenyl radical or an ortho-fused bicycliccarbocyclic radical of nine of ten ring atoms in which at least one ringis aromatic, which radical Ar may be unsubstituted or may bear one ormore substituents selected from halo, cyano, trifluoromethyl,(1-4C)alkyl, (1-4C)alkoxy, methylenedioxy, hydroxy, mercapto, --S(O)_(n)R^(xa), (1-5C)alkanoyl, (1-5C)alkanoyloxy, nitro, NR^(xb) R^(xc),NR^(xd) R^(xe), C(═NR^(xf))NR^(xg) R^(xh), CONR^(xb) R^(xc) andCOOR^(xj) wherein n is the integer 0, 1, or 2; R^(xa) is (1-6C)alkyl,(3-6C)cycloalkyl or phenyl (which phenyl may bear a halo,trifluoromethyl, (1-3C)alkyl or (1-3C)alkoxy substitutent); the radicalNR^(xb) R^(xc) contains zero to seven carbons and each of R^(xb) andR^(xc) is independently hydrogen, (1-5C)alkyl or (3-6C)cycloalkyl, orthe radical NR^(xb) R^(xc) is pyrrolidino, piperidino, morpholino,thiomorpholine (or its S-oxide) or piperazinyl (which piperazinyl maybear a (1-3C)alkyl substituent at the 4-position); and wherein R^(xd) ishydrogen or (1-4C)alkyl and R^(xe) is (1-5C)alkanoyl, benzoyl; or agroup of formula C(═J^(x))NR^(xg) R^(xh) in which J^(x) is oxygen,sulfur, NR^(xf) or CHR^(xi) ; R^(xf) is hydrogen, (1-5C)alkyl ortogether with R^(xg) forms an ethylene or trimethylene diradical, theradical NR^(xg) R^(xh) contains zero to 7 carbons and each of R^(xg) amdR^(xh) is independently hydrogen, (1-5C)alkyl or (3-6C)cycloalkyl, orthe radical NR^(xg) R^(xh) is pyrrolidino, piperidino, morpholino,thiomorpholino (or its S-oxide) or piperazinyl (which piperazinyl maybear a (1-3C)alkyl substituent at the 4-position); or R^(xg) togetherwith R^(xf) forms an ethylene or trimethylene diradical and R^(xh) ishydrogen or (1-5C)alkyl; R^(xi) is cyano, nitro, (1-5C)alkylsulfonyl orphenylsulfonyl; and R^(xj) is hydrogen, (1-5C)alkyl or benzyl; and Hetis a radical (or stable N-oxide thereof) attached via a ring carbon of amonocyclic aromatic ring containing five or six ring atoms consisting ofcarbon and one to four heteroatoms selected from oxygen, sulfur andnitrogen, or an ortho-fused bicyclic heterocycle derived therefrom byfusing a propenylene, trimethylene, tetramethylene or benz-diradical,which radical Het may be unsubstituted or may be substituted on carbonby one or more of the substituents defined above for Ar and may besubstituted on nitrogen by (1-3C)alkyl;

Q² and Q³ are independantly hydrogen or (1-3C)alkyl;

Q⁴ is phenyl which may bear one or two substituents independentlyselected from halo, trifluoromethyl, hydroxy, (1-3C)alkoxy, (1-3C)alkyland methylenedioxy; or Q⁴ is thienyl, imidazolyl, benzo[b]thiophenyl ornaphthyl any of which may bear a halo substituent; or Q⁴ is biphenylyl;or Q⁴ is carbon-linked indolyl which may bear a benzyl substituent atthe 1-position; and

Q⁵ is formyl, 4-imidazolidinyl, 3-pyrrolidinyl (wherein the nitrogen mayoptionally be substituted by a substituent selected from (1-3C)alkyl,acyl, and benzyloxycarbonylaminoacetyl), (3-6C)cycloalkyl,trifluoromethyl, 4-piperidino (wherein the nitrogen may optionally besubstituted by a substituent selected from (1-3C)alkyl, and acyl), aryl,heteroaryl, pyrid-1-ylmethyl, fluorenyl, β-styryl, a radical of formulaXII-XXII or xanthenyl; or Q⁵ is (1-8C)alkyl which may be substituted by0-3 substituents selected from aryl, heteroaryl, (aryl)oxy,aryl(1-3C)-alkyl, heteroaryl(1-3C)alkyl, (1-6C)alkyl, (heteroaryl)oxy,benzyloxy, (3-6C)cycloalkyl, adamantyl, norbornanyl, β-styryl, cyano,trifluoromethyl, oxo, hydroxy, (1-4C)alkoxy, --NR^(a) R^(b),--NC(═O)NR^(c) R^(d), --NC(═O)OR^(e), --C(═O)OR^(f), --S(O)R^(g),--S(O)₂ R^(h), ═NR^(i), SR^(j), and the radicals of formulae XII-XXII;

R^(a) -R^(b) are independently selected from hydrogen, acyl, formyl, and(1-4C)alkyl, or the group NR^(a) R^(b) may form a cyclic group selectedfrom pyrrolidino, piperidino, morpholino, thiomorpholino (or itsS-oxide) or piperazinyl (which piperazinyl may bear a (1-3C)alkylsubstituent at the 4-position);

R^(c) -R^(f) and R^(j) are independently selected from hydrogen, phenyl,benzyl, phenethyl and (1-4C)alkyl;

R^(g) and R^(h) are independently selected from hydrogen, phenyl,benzyl, phenethyl, β-styryl and (1-4C)alkyl;

R^(i) is hydrogen, (1-4C)alkyl, acyl or (1-4C)alkoxy;

wherein any aryl or heteroaryl in, or any aryl or heteroaryl portion of,Q⁵, or any aryl or heteroaryl portion of R^(a) -R^(j), may beunsubstituted or may bear 1-5 substituents selected from halo, cyano,trifluoromethyl, (1-4C)alkyl, (1-4C)alkoxy, methylenedioxy, phenoxy,benzyloxy, NR^(k) R^(m), --NS(O)₂ aryl (wherein the aryl group may besubstituted by 0-3 (1-3C)alkyl groups), hydroxy, --SR^(n), and nitro;and wherein any β-styryl may optionally be substituted at the β-positionby a substituent selected from (1-3C)alkoxy;

wherein R^(k) -R^(m) are independently selected from hydrogen, acyl,formyl, and (1-4C)alkyl, or the group NR^(k) R^(m) may form a cyclicgroup selected from pyrrolidino, piperidino, morpholino, thiomorpholino(or its S-oxide) or piperazinyl (which piperazinyl may bear a(1-3C)alkyl substituent at the 4-position); and

R^(n) is hydrogen or (1-3C)alkyl;

or the N-oxide of a piperidino nitrogen in Q¹ indicated by Δ in formulaeIa-Im (or of either basic piperazinyl nitrogen of Q¹ when Z^(a) isnitrogen);

or a pharmaceutically acceptable salt thereof;

or a quaternary ammonium salt thereof in which the piperidino nitrogenin Q¹ indicated by Δ in formulae Ia-Im (or either basic piperazinylnitrogen of Q¹ when Z^(a) is nitrogen) is a quadricovalent ammoniumnitrogen wherein the fourth radical on the nitrogen R¹ is (1-4C)alkyl orbenzyl and the associated counterion A is a pharmaceutically acceptableanion;

provided that when Q¹ is a pyrrolidino or piperidino radical of formulaId, Q⁴ is not phenyl, 3,4-dimethoxyphenyl, 3,4-(methylenedioxy)phenyl,3-methoxyphenyl, or 2-thienyl.

A preferred sub-group of compounds of the invention are compounds offormula I as defined above, wherein Q⁵ is aryl, or heteroaryl; or Q⁵ isa radical of formula III wherein: a) R¹ is aryl, heteroaryl,aryl(1-3C)alkyl or heteroaryl(1-3C)alkyl; and R² and R³ areindependantly hydrogen, aryl, heteroaryl, aryl(1-3C)alkyl,heteroaryl(1-3C)alkyl, (1-6C)alkyl or (3-6C)cycloalkyl; or b) R¹ and R²together with the carbon to which they are attached form a(3-6C)cycloalkyl and R³ is hydrogen or (1-6C)alkyl; wherein any aryl orheteroaryl ring in Q⁵ may be unsubstituted or may bear one or moresubstituents selected from halo, cyano, trifluoromethyl, (1-4C)alkyl,(1-4C)alkoxy, methylenedioxy, hydroxy and nitro;

or the N-oxide of a piperidino nitrogen in Q¹ indicated by Δ in formulaeIa-Im (or of either basic piperazinyl nitrogen of Q¹ when Z^(a) isnitrogen);

or a pharmaceutically acceptable salt thereof;

or a quaternary ammonium salt thereof in which the piperidino nitrogenin Q¹ indicated by Δ in formulae Ia-Im (or either basic piperazinylnitrogen of Q¹ when Z^(a) is nitrogen) is a quadricovalent ammoniumnitrogen wherein the fourth radical on the nitrogen R¹ is (1-4C)alkyl orbenzyl and the associated counterion A is a pharmaceutically acceptableanion.

It will be appreciated that a compound of formula I may contains one ormore asymmetically substituted carbon atoms and that such a compound maybe isolated in optically active, racemic and/or diastereomeric forms. Acompound may exhibit polymorphism. It is to be understood that thepresent invention encompasses any racemic, optically-active,diastereomeric, polymorphic or stereoisomeric form, or mixture thereof,which form possesses NK1 and NK2 antagonist properties, it being wellknown in the art how to prepare optically-active forms (for example, byresolution of the racemic form or by synthesis from optically-activestarting materials) and how to determine the NK1 and NK2 antagonistproperties by the standard tests known in the art and those describedhereinafter.

In this specification R^(a), R^(b), R¹, R², et cetera stand for genericradicals and have no other significance. It is to be understood that thegeneric terms "(1-3C)alkyl" and "(1-6C)alkyl" include both straight andbranched chain alkyl radicals but references to individual alkylradicals such as "propyl" embrace only the straight chain ("normal")radical, branched chain isomers such as "isopropyl" being referred tospecifically. A similar convention applies to other generic groups, forexample, alkoxy, alkanoyl, et cetera. Halo is fluoro, chloro, bromo oriodo. Aryl denotes a phenyl radical or an ortho-fused bicycliccarbocyclic radical having about nine to ten ring atoms in which atleast one ring is aromatic. Heteroaryl encompasses a radical attachedvia a ring carbon of a monocyclic aromatic ring containing five ringatoms consisting of carbon and one to four heteroatoms selected fromoxygen, sulfur and nitrogen or containing six ring atoms consisting ofcarbon and one or two nitrogens, as well as a radical of an ortho-fusedbicyclic heterocycle of about eight to ten atoms derived therefrom,particularly a benz-derivative or one derived by fusing a propenylene,trimethylene of tetramethylene diradical thereto, as well as a stableN-oxide thereof.

Particular values are listed below for radicals, substituents and rangesfor a compound of formula I as described above for illustration only andthey do not exclude other defined values or other values within definedranges for the radicals and substituents.

A particular value for Ar is phenyl which may be unsubstituted or maybear a chloro, methyl, methoxy, hydroxy or methylsulfinyl substituent. Aparticular value for Het is furyl, thienyl, 2-imidazolyl,1,3,4-oxadiazol-2-yl, pyridyl or pyrimidinyl which ring may beunsubstituted or may bear a chloro, methyl, methoxy, hydroxy,methylsulfinyl, methoxycarbonyl or ethoxycarbonyl substituent. Aparticular value for aryl is phenyl. A particular value for heteroarylis furyl, pyridyl or pyrimidinyl. A particular value for halo is chloroor bromo. A particular value for (1-3C)alkyl is methyl, ethyl, propyl orisopropyl; for (1-4C)alkyl is methyl, ethyl, propyl, isopropyl, butyl,isobutyl or t-butyl; for (1-5C)alkyl is methyl, ethyl, propyl,isopropyl, butyl, isobutyl, t-butyl, pentyl or isopentyl; for(1-6C)alkyl is methyl, ethyl, propyl, isopropyl, butyl, isobutyl,t-butyl, pentyl, isopentyl, hexyl or isohexyl; and for (1-8C)alkyl ismethyl, ethyl, propyl, isopropyl, isopentyl, 1-ethylpropyl, hexyl,isohexyl, 1-propylbutyl, or octyl. A particular value for(3-6C)cycloalkyl is cyclopropyl, cyclopentyl or cyclohexyl; for(3-7C)cycloalkyl is cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl;and for (3-8C)cycloalkyl is cyclopropyl, cyclopentyl, cyclohexyl,cycloheptyl or cyclooctyl. A particular value for (3-6C)alkenyl isallyl, 2-butenyl or 3-methyl-2-butenyl. A particular value for(1-4C)alkanoyl is formyl, acetyl, propionyl, butyryl or isobutyryl; andfor (1-5C)alkanoyl is formyl, acetyl, propionyl, butyryl, isobutyryl,valeryl, isovaleryl or pivaloyl.

A more particular value for Ar is phenyl which may be unsubstituted ormay bear a methoxy, hydroxy or methylsulfinyl substituent. A moreparticular value for Het is pyridyl or pyrimidinyl which ring may beunsubstituted or may bear a methoxy, hydroxy or methylsulfinylsubstituent. A more particular value for heteroaryl is pyridyl. A moreparticular value for halo is chloro. A more particular value for(1-3C)alkyl is methyl; for (1-4C)alkyl is methyl or ethyl; for(1-5C)alkyl is methyl, ethyl, propyl or isopropyl; for (1-6C)alkyl ismethyl, ethyl, propyl, isopropyl, butyl, isobutyl or t-butyl; and for(1-8C)alkyl is methyl, ethyl, propyl, isopropyl, 1-ethylpropyl or1-propylbutyl. A more particular value for (3-6C)cycloalkyl iscyclopropyl or cyclopentyl; for (3-7C)cycloalkyl is cyclopropyl orcyclopentyl; and for (3-8C)cycloalkyl is cyclopropyl, cyclopentyl,cyclohexyl or cycloheptyl. A more particular value for (3-6C)alkenyl isallyl. A more particular value for (1-4C)alkanoyl is formyl or acetyl;and for (1-5C)alkanoyl is formyl, acetyl, propionyl, butyryl orisobutyryl.

A particular value for Q¹ is 4-hydroxy-4-phenylpiperidino,4-acetamido-4-phenylpiperidino, 4-(benzylsulfinyl)-4-methoxy-piperidino,4-(2-methylsulfinylphenyl)piperidino, or4-(2-oxoperhydropyrimidin-1-yl)piperidino; Q² is methyl, ethyl orpropyl; for Q³ is hydrogen; for Q⁴ is 3,4-dichlorophenyl or3,4-methylenedioxyphenyl; and for Q⁵ is phenyl, benzyl, 2-methoxyphenyl,3,5-bis(trifluoro-methyl)benzyl, 2-isopropoxybenzyl and3,5-bis(trifluoromethyl)phenyl.

A particular group of compounds of formula I are compounds wherein Q¹ isa radical selected from the group of radicals of formulae Ia, Ib, Ic,Ie, If, Ig, Ih, Ij, Ik and Im,

A particular group of compounds of formula I are compounds wherein Q¹ isselected from radicals of formulae Ie, If, Ig, Ih, Ij Ik and Im.

A particular group of compounds of formula I are compounds of formulaVIII wherein, Q¹ is 4-hydroxy-4-phenylpiperidino,4-acetamido-4-phenylpiperidino, 4-(benzylsulfinyl)-4-methoxy-piperidino,or 4-(₂ -oxoperhydropyrimidin-1-yl)piperidino; Q² is (1-3C)alkyl; and Q⁵is phenyl, benzyl, 2-methoxyphenyl, 2-methoxybenzyl,3,5-bis(trifluoromethyl)phenyl, 3,5-bis(trifluoro-methyl)benzyl,3,5-dimethylphenyl, 3,5-dimethylbenzyl, 3,5-dichloro-phenyl,3,5-dichlorobenzyl, 3,5-dimethoxyphenyl, or 3,5-dimethoxybenzyl.

A particular group of compounds of formula I are compounds wherein Q⁵ isformyl, 4-imidazolidinyl, 3-pyrrolidinyl (wherein the nitrogen mayoptionally be substituted by a substituent selected from (1-3C)alkyl,acyl, and benzyloxycarbonylaminoacetyl), (3-6C)cycloalkyl,trifluoromethyl, 4-piperidino (wherein the nitrogen may optionally besubstituted by a substituent selected from (1-3C)alkyl, and acyl), aryl,heteroaryl pyrid-1-ylmethyl, fluorenyl, β-styryl, a radical of formulaXII-XXII or xanthenyl; or Q⁵ is (1-6C)alkyl which may be substituted byone substituent selected from aryl, heteroaryl, (aryl)oxy,(heteroaryl)oxy, benzyloxy, (3-6C)cycloalkyl, adamantyl, norbornanyl,β-styryl, cyano, trifluoromethyl, oxo, hydroxy, (1-4C)alkoxy, --NR^(a)R^(b), --NC(═O)NR^(c) R^(d), --NC(═O)OR^(e), --C(═O)OR^(f), --S(O)R^(g),--S(O)₂ R^(h), ═NR^(i), SR^(j), and the radicals of formulae XII--XXII.

A more particular group of compounds of formula I are compounds offormula VIII wherein, Q¹ is 4-hydroxy-4-phenylpiperidino; Q² is(1-3C)alkyl; and Q⁵ is phenyl, benzyl, 2-methoxyphenyl,3,5-bis(trifluoromethyl)benzyl, 2-isopropoxybenzyl or3,5-bis(trifluoromethyl)phenyl.

Another more particular group of compounds of formula I are compounds offormula VIII wherein, Q¹ is 4-hydroxy-4-phenylpiperidino; Q² is methyl;and Q⁵ is phenyl, benzyl, 2-methoxyphenyl, 2-methoxybenzyl,3,5-bis(trifluoromethyl)phenyl, 3,5-bis(trifluoro-methyl)benzyl,3,5-dimethylphenyl, 3,5-dimethylbenzyl, 3,5-dichloro-phenyl,3,5-dichlorobenzyl, 3,5-dimethoxyphenyl, or 3,5-dimethoxybenzyl.

Pharmaceutically acceptable salts of a compound of formula I includethose made with a strong inorganic or organic acid which affords aphysiologically acceptable anion, such as, for example, hydrochloric,sulfuric, phosphoric, methanesulfonic, or para-toluenesulfonic acid.

A compound of formula I may be made by processes which include processesknown in the chemical art for the production of structurally analogousheterocyclic compounds. Such processes and intermediates for themanufacture of a compound of formula I as defined above are provided asfurther features of the invention and are illustrated by the followingprocedures in which the meanings of generic radicals are as definedabove unless otherwise indicated:

(a) acylation of an amine of formula IV with an acid chloride of formulaV wherein X is chloro. The acylation may conveniently be carried out inan inert solvent such as for example dimethylformamide, dichloromethane,chloroform, tetrahrdrofuran, toluene or diethyl ether, at a temperaturein the range of -50 to 100 ° C., preferably in the range of -20 to 50°C.; and may conveniently be carried out in the presence of a suitablebase. Suitable conditions for the acylation of an amine of formula IVare described in Example 1.

(b) acylation of an amine of formula IV with an acid of formula Vwherein X is OH. The reaction may be carried out in the presence of asuitable coupling reagent, such as for example 1,1'carbonyldiimidazole,in an inert solvent, such as for example tetrahydrofuran, toluene ordiethyl ether, at a temperature in the range of -50 to 100° C.,preferably in the range of 0 to 50° C. Suitable conditions for theacylation of an amine of formula IV are described in Example 2.

(c) for a compound of formula I wherein Q² is (1-3C)alkyl, alkylating acorresponding compound of formula I wherein Q² is hydrogen with acompound of formula Q² Y wherein Y is a suitable leaving group such forexample chloro, bromo or methanesulfonyl. The alkylation mayconveniently be carried out in an inert solvent such as for exampledichloromethane, chloroform, tetrahrdrofuran, toluene or diethyl ether,at a temperature in the range of -50 to 100° C., preferably in the rangeof -20 to 50° C., and may conveniently be carried out in the presence ofa suitable base. Suitable conditions for the alkylation of a compound offormula I are described in Example 3.

(d) For an N-oxide of a piperidino nitrogen in Q¹ indicated by Δ informulae Ia-Im (or of either basic piperazinyl nitrogen of Q¹ when Z^(a)is nitrogen); oxidizing the piperidino nitrogen of a correspondingcompound of formula I using a conventional procedure, such as, forexample, using hydrogen peroxide in methanol, peracetic acid,3-chloroperoxybenzoic acid in an inert solvent (such as dichloromethane)or dioxirane in acetone.

(e) For a quaternary ammonium salt of the piperidino nitrogen in Q¹indicated by Δ in formulae Ia-Im (or either basic piperazinyl nitrogenof Q¹ when Z^(a) is nitrogen), alkylating the piperidino nitrogen in acorresponding compound of formula I with an alkylating agent of formulaR¹ Y wherein Y is a leaving group.

(f) For a compound of formula I which bears a sulfinyl group, oxidizingthe sulfur of a corresponding compound of formula I which bears asulfide group using a conventional method.

(g) For a compound of formula I which bears a sulfonyl group, oxidizinga sulfide or sulfinyl group of a corresponding compound of formula Iusing a conventional method.

(h) For a compound of formula I which bears an aromatic hydroxy group,cleaving the ether of a corresponding compound of formula I which bearsan aromatic alkoxy group using a conventional method.

It may be desired to optionally use a protecting group during all orportions of the above described processes; the protecting group then maybe removed when the final compound is to be formed.

Whereafter, for any of the above procedures, when a pharmaceuticallyacceptable salt of a compound of formula I is required, it may beobtained by reacting the compound of formula I with an acid affording aphysiologically acceptable counterion or by any other conventionalprocedure.

It will also be appreciated that certain of the various optionalsubstituents in the compounds of the invention may be introduced bystandard aromatic substitution reactions or generated by conventionalfunctional group modifications either prior to or immediately followingthe processes above, and as such are included in the process aspect ofthe invention. The reagents and reaction conditions for such proceduresare well known in the chemical art.

If not commercially available, the necessary starting materials for theabove procedures may be made by procedures which are selected fromstandard techniques of organic chemistry, techniques which are analogousto the synthesis of known, structurally similar compounds and techniqueswhich are analogous to the above described procedures or the proceduresdescribed in the Examples. The starting materials and the procedures fortheir preparation are additional aspects of the invention.

A convenient intermediate for the preparation of a compound of formula Iis an amine of formula IV, which can be prepared as shown in Scheme I,from a piperidine of formula Q¹ -H, wherein Q¹ is selected from formulaeIa-Im. Coupling of an aldehyde of formula VI with trimethylsilylcyanideand a piperidine of formula Q¹ -H in the presence of catalytic zinciodide gives a nitrile of formula VII. Reduction of the nitrile yieldsan amine of formula IV, wherein Q² is hydrogen.

Piperidines of formula Q¹ -H can be pepared from readily availablestarting materials using known synthetic methods. For example, thepreparation of piperidines of formula Q¹ -H is disclosed in EuropeanPatent Application, Publication Number (EPA) 428434, EPA 474561, EPA512901, EPA 512902, EPA 515240 and EPA 559538, as well as in WO94/10146. As will be clear to one skilled in the art, a variety ofsequences are available for preparation of the starting materials, andthe sequences leading to the starting materials and products of theinvention may be altered if appropriate considerations regarding thesynthetic methods and radicals present are followed.

The utility of a compound of the invention or a pharmaceuticallyacceptable salt thereof (hereinafter, collectively referred to as a"Compound") may be demonstrated by standard tests and clinical studies,including those disclosed in the EPA publications noted above, and thosedescribed below.

SP Receptor Binding Assay (Test A)

The ability of a Compound of the invention to antagonize the binding ofSP at the NK1 receptor may be demonstrated using an assay using thehuman NK1 receptor expressed in Mouse Erythroleukemia (MEL) cells. Thehuman NK1 receptor was isolated and characterized as described in: B.Hopkins, et al. "Isolation and characterization of the human lung NK1receptor cDNAN" Biochem. Biophys. Res. Comm., 1991, 180, 1110-1117; andthe NK1 receptor was expressed in Mouse Erythroleukemia (MEL) cellsusing a proceedure similar to that described in Test B below.

In general, the Compounds of the invention which were testeddemonstrated statistically significant binding activity in Test A with aK_(i) of 1 μM or much less typically being measured.

Neurokinin A (NKA) Receptor Binding Assay (Test B)

The ability of a Compound of the invention to antagonize the binding ofNKA at the NK2 receptor may be demonstrated using an assay using thehuman NK2 receptor expressed in Mouse Erythroleukemia (MEL) cells, asdescribed in: Aharony, D., et al. "Isolation and PharmacologicalCharacterization of a Hampster Neurokinin A Receptor cDNA" MolecularPharmacology, 1994, 45, 9-19. In an initial use of this assay, the IC₅₀measured for the standard compound L-659,877 was found to be 30 nMversus ³ H-NKA binding to MELM.

The selectivity of a Compound for binding at the NK1 and the NK2receptors may be shown by determining its binding at other receptorsusing standard assays, for example, one using a tritiated derivative ofNKB in a tissue preparation selective for NK3 receptors. In general, theCompounds of the invention which were tested demonstrated statisticallysignificant binding activity in Test B with a K_(i) of 10 μM or lesstypically being measured.

Rabbit Pulmonary Artery: NK1 in vitro Functional Assay (Test C)

The ability of a Compound of the invention to antagonize the action ofthe agonist, Ac-[Arg⁶, Sar⁹, Met(O₂)¹¹ ]SP(6-11) (designated ASMSP) in apulmonary tissue may be demonstrated using a functional assay which iscarried out under conditions similar to those described in: Emonds-Alt,X., et al. "In vitro and in vivo biological activities of Sr 140333, anovel potent non-peptide tachykinin NK₁ receptor antagonist" Eur. J.Pharmacol., 1993, 250, 403-413; and which is carried out as follows.

Male New Zealand white rabbits are killed by lethal injection (Nembutal,60 mg/kg into a cannulated ear vein). Heparin, 0.0025 ml/kg of a 1000U/ml solution, is injected into the ear vein prior to nembutal in orderto decrease blood coagulation. The left and right branches of thepulmonary artery are isolated from the rest of the lung tissue and cutin half to provide four ring segments from each animal. The segments,with intact endothelium, are suspended between stainless steel stirrupsand placed in water-jacketed (37.0° C.) tissue baths containingphysiological salt solution of the following composition (mM): NaCl,119.0; KCl4.6; CaCl₂, 1.8; MgCl₂, 0.5; NaH₂ PO₄, 1.0; NaHCO₃,25.0;glucose 11.0; indomethacin 0.005 (to inhibit cyclooxygenase); anddl-propranolol, 0.001 (to inhibit β-adrenergic receptors); gassedcontinuously with 95% O₂ -5% CO₂. Initial tension placed on each tissueis 2 grams, which is maintained throughout a 0.5 hour equilibrationperiod. Changes in tension are measured on a Grass polygraph via GrassFT-03 force transducers.

Thiorphan, 1×10⁻⁶ M (to inhibit E.C.3.4.24.11), and a selective NK2antagonist (to inhibit NK2 receptors) such as for example, an antagonistdescribed in WO 94/148,184, EPA 0625509, EPA 0630887, or the antgonistSR48968 (3×10₋₈ M), are added to the tissue baths along with the testcompound or its vehicle 90 minutes before the NK₁ receptor agonist,Ac-[Arg⁶,Sar⁹,Met(O₂)¹¹ ]SP(6-11) (designated ASMSP). Phenylephrine,3×10⁻⁶ M, is added in order to induce tone in the tissue. One hour afterintroducing phenylephrine, cumulative concentration response effects ofASMSP are obtained and papaverine, 1×10⁻³ M, is added at the end of eachexperiment to determine the maximum magnitude of relaxation (defined as100%).

Potencies of the compounds are determined by calculating the apparentdissociation constants (KB) for each concentration tested using thestandard equation:

    K.sub.B =[antagonist]/(dose ratio-1)

where dose ratio=antilog[(agonist-log molar EC₅₀ withoutcompound)-(agonist-log molar EC₅₀ with compound)]. The K_(B) values areconverted to the negative logarithms and expressed as -log molar K_(B)(i.e. pK_(B)). The potency of the agonist is determined at 50% of itsown maximum relaxation in each curve. The EC₅₀ values are converted tonegative logarithms and expressed as -log molar EC₅₀. Maximum relaxationresponses to ASMSP are determined by expressing the maximum response tothe agonist as a percentage of the relaxation caused by papaverine.

Guinea Pig Trachea Assay: NK2 in vitro Functional Assay (Test D)

The ability of a Compound of the invention to antagonize the action ofthe agonist, [β-Ala8]-Neurokinin A(4-10) (designated BANK), in apulmonary tissue may be demonstrated using a functional assay in guineapig trachea which is carried out under conditions similar to thosedescribed in: Ellis, J. L., et al., "Pharmacological examination ofreceptors mediating contractile responses to tachykinins in airwaysisolated from human, guinea pig and hamsters" J. Pharmacol. Exp. Ther.,1993, 267, 95-101; and which is carried out as follows.

Male guinea pigs are killed by a sharp blow to the back of the headfollowed by exsanguination. The trachea are removed, trimmed of excesstissue (including removal of epithelium) and cut in spiral fashion. Eachlongitudinally cut tracheal segment is suspended as a strip in awater-jacketed (37.5° C.) tissue bath containing a physiological saltsolution of the following composition (mM): NaCl, 119; KCl 4.6; CaCl₂,1.8; MgCl₂, 0.5; NaH₂ PO₄, 1; NaHCO3, 25; glucose, 11; and indomethacin,0.005 (to inhibit cyclooxygenase); gassed continuously with 95% O2-5%CO₂. Initial tension placed on each tissue is 5 g, which is maintainedthroughout a 0.5 hour equilibration period before addition of otherdrugs. Contractile responses are measured on a Grass polygraph via GrassFT-03 force transducers.

Tissues are challenged once with a single concentration of capsaicin(1×10⁻⁶ M) and washed extensively before addition of a selective NK1antagonist, such as for example (±)--CP96345 (3×10⁻⁷ M) (to block NK1receptors) and thiorphan, 1×10⁻⁶ M (to block E.C.3.4.24.11). Cumulativeaddition of the NK₂ agonist [β-Ala8]-Neurokinin A(4-10) (designatedBANK) is begun 35 minutes after addition of thiorphan. Test compound isadded 120 min before BANK.

Potencies of the compounds are evaluated by calculating apparentdissociation constants (K_(B)) for each concentration tested using thestandard equation:

    K.sub.B =[antagonist]/(dose ratio-1)

where dose ratio=antilog[(agonist-log molar EC₅₀ withoutcompound)-(agonist-log molar EC₅₀ with compound)]. The K_(B) values areconverted to the negative logarithms and expressed as -log molar K_(B)(i.e. pK_(B)). The potency of BANK is determined at 50% of its ownmaximum response level in each curve. The EC₅₀ values are converted tothe negative logarithms and expressed as -log molar EC₅₀. Maximumcontractile responses to BANK are determined by expressing the maximumresponse to BANK as a percentage of the initial contraction caused bycapasacin.

In general, the Compounds of the invention which were testeddemonstrated functional activity in Tests C and D, with a pKB of 5 orgreater typically being measured in each test. For Example, the compoundof Example 2 demonstrated a pKB of 6.2 in Test C.

Guinea Pig Labored Abdominal Breathing (Dyspnea) Assay: NK₁ and NK₂ invivo Functional Assay (Test E)

The activity of a compound as an antagonist of NK₁ or NK₂ receptors alsomay be demonstrated in vivo in laboratory animals, for example byadapting a routine guinea pig aerosol test described for evaluation ofleukotriene antagonists in: Snyder, et al. "Conscious guinea-pig aerosolmodel for evaluation of peptide leukotriene antagonists" J. Pharmacol.Meth., 1988, 19, 219, which is carried out as follows.

Using the clear plastic chamber described previously by Snyder et al. tosecure guinea pigs for a head-only aerosol exposure tobronchoconstrictor agonists, agonist is administered by aerosol to sixconscious guinea pigs simultaneously during each maneuver. Thetachykinin NK₁ -selective agonist ASMSP or the tachykinin NK₂ -selectiveagonist, BANK, 3×10⁻⁵ M of either, is aerosolized from a Devilbiss Model25 ultrasonic nebulizer into an air stream entering the chamber at arate of 2 L/minute.

Guinea pigs (275-400 g) are fasted for approximately 16 hours prior toexperimentation. Compounds to be evaluated for blockade of effects ofASMSP or BANK or their vehicle (10% PEG400 in saline) are given by p.o.,i.v. or aerosol routes of administration at various times before aerosolagonist challenge. All animals are pretreated with atropine (10 mg/kg,i.p., 45 minutes pretreatment) indomethacin (10 mg/kg, i.p. 30 minutespretreatment), propranolol (5 mg/kg, i.p., 30 minutes pretreatment), andthiorphan (1 mg/ml aerosol for 5 minutes, 15 minutes pretreatment).

Aerosol challenge with the agonist produces an initial increase inrespiratory rate followed by a decrease with early signs of minorinvolvement of the abdominal muscles. The respiratory rate decreasesfurther and the breathing becomes more labored with greater involvementof the abdominal muscles as exposure continues. The distinctlyrecognizable end point is the point where the breathing pattern of theguinea pig is consistently slow, deep, and deliberate, showing markedinvolvement of the abdominal muscles. Time, in seconds, from the onsetof aerosol challenge to this end point is determined for each animal byusing a stopwatch. The animals generally collapsed after reaching theend point and did not recover from the agonist-induced respiratorydistress. Antagonists result in an increase in the time to reach the endpoint. Animals receive the aerosol administration of agonist for amaximum time of 780 seconds.

Differences between drug-treated groups and correspondingvehicle-treated control groups are compared using Student's t-test forunpaired observations. Results are reported as % protection values,where % protection=

    [(drug time-mean control time)/(maximal aerosol time-mean control time)]×100

Clinical Studies

Clinical studies to demonstrate the efficacy of a Compound of theinvention may be carried out using standard methods. For example, theability of a Compound to prevent or treat the symptoms of asthma orasthma-like conditions may be demonstrated using a challenge of inhaledcold air or allergen and evaluation by standard pulmonary measurementssuch as, for example, FEV₁ (forced expiratory volume in one second) andFVC (forced vital capacity), analyzed by standard methods of statisticalanalysis.

It will be appreciated that the implications of a Compound's activity inthe above desribed Tests is not limited to asthma, but rather, that theTests provide evidence of general antagonism of both SP and NKA

SP and NKA have been implicated in the pathology of numerous diseasesincluding: rheumatoid arthritis, Alzheimer's disease, oedema, allergicrhinitis, inflamation pain, gastrointestinal-hypermotility, irritablebowel syndrome, anxiety, emesis, Huntington's Disease, Psycoses,hypertension, migraine, urinary incontinence, bladder hypermotility, anduticaria. Accordingly, one feature of the invention is the use of acompound of formula I or a pharmaceutically acceptable salt thereof inthe treatment of a disease in a human or other mammal in need thereof inwhich SP or NKA is implicated and antagonism of its action is desired.

Asthma is characterized symptomatically by both chronic inflammation andhyperresponsiveness of the airways. The NK1 receptor is known to mediateinflammation and mucus hypersecretion in airways; and the NK2 receptoris involved in the control of the tone of bronchial smooth muscle. Thus,agents capable of antagonizing the actions of SP and NKA, at the NK1 andNK2 receptors, respectively, are capable of reducing both the chronicinflammation and the airway hyperresponsiveness which are symptomatic ofasthma. Additionally, a synergistic effect against bronchoconstrictionmay result from the simultaneous application of an NK1 antagonist and anNK2 antagonist. D. M. Foulon, et al. "NK1 and NK2 Receptors MediatedTachykinin and Resiniferatoxin-induced Bronchospasm in Guinea Pigs"American Review of Respiratory Disease, 1993, 148, 915-921. Accordingly,another feature of the invention is the use of a compound of formula Ior a pharmaceutically acceptable salt thereof in the treatment of asthmain a human or other mammal in need thereof.

Because of the range of effects attributable to the actions of SP andNKA, compounds which are capable of blocking their actions may also beuseful as tools for further evaluating the biological actions of otherneurotransmitters in the Tachykinin family. As a result, another featureof the invention is provided by the use of a compound of formula I or asalt thereof as a pharmacological standard for the development andstandardization of new disease models or assays for use in developingnew therapeutic agents for treating diseases in which SP or NKA areimplicated or for assays for their diagnosis.

When used in the treatment of a disease, a compound of the invention isgenerally administered as an appropriate pharmaceutical compositionwhich comprises a compound of formula I or a pharmaceutically acceptablesalt thereof as defined hereinbefore and a pharmaceutically acceptablediluent or carrier, the composition being adapted for the particularroute of administration chosen. Such a composition is provided as afurther feature of the invention. It may be obtained employingconventional procedures and excipients and binders, and it may be one ofa variety of dosage forms. Such forms include, for example, tablets,capsules, solutions or suspensions for oral administration;suppositories for rectal administration; sterile solutions orsuspensions for administration by intravenous or intramuscular infusionor injection; aerosols or nebulizer solutions or suspensions foradministration by inhalation; or powders together with pharmaceuticallyacceptable solid diluents such as lactose for administration byinsufflation.

For oral administration a tablet or capsule containing up to 250 mg (andtypically 5 to 100 mg) of a compound of formula I may conveniently beused. For administration by inhalation, a compound of formula I will beadministered to humans in a daily dose range of, for example, 5 to 100mg, in a single dose or divided into two to four daily doses. Similarly,for intravenous or intramuscular injection or infusion a sterilesolution or suspension containing up to 10% w/w (and typically 0.05 to5% w/w) of a compound of formula I may conveniently be used.

The dose of a compound of formula I to be administered will necessarilybe varied according to principles well known in the art taking accountof the route of administration and the severity of the condition and thesize and age of the patient under treatment. However, in general, thecompound of formula I will be administered to a warm-blooded animal(such as man) so that a dose in the range of, for example, 0.01 to 25mg/kg (and usually 0.1 to 5 mg/kg) is received. It will be understoodthat generally equivalent amounts of a pharmaceutically acceptable saltof a compound of formula I may be used.

The invention will now be illustrated by the following non-limitingexamples in which, unless stated otherwise:

(i) temperatures are given in degrees Celsius (° C.); operations werecarried out at room or ambient temperature, that is, at a temperature inthe range of 18-25° C.;

(ii) organic solutions were dried over anhydrous magnesium sulfate;evaporation of solvent was carried out using a rotary evaporator underreduced pressure (600-4000 pascals; 4.5-30 mm Hg) with a bathtemperature of up to 60° C.;

(iii) chromatography means chromatography on silica gel; thin layerchromatography (TLC) was carried out on silica gel plates;

(iv) in general, the course of reactions was followed by TLC andreaction times are given for illustration only;

(v) melting points are uncorrected and (dec) indicates decomposition;the melting points given are those obtained for the materials preparedas described; polymorphism may result in isolation of materials withdifferent melting points in some preparations;

(vi) final products had satisfactory proton nuclear magnetic resonance(NMR) spectra;

(vii) yields are given for illustration only and are not necessarilythose which may be obtained by diligent process development;preparations were repeated if more material was required;

(viii) when given, NMR data is in the form of delta values for majordiagnostic protons, given in parts per million (ppm) relative totetramethylsilane (TMS) as an internal standard, determined at 300 MHzusing perdeuterio dimethyl sulfoxide (DMSO-d₆) as solvent; conventionalabbreviations for signal shape are used; for AB spectra the directlyobserved shifts are reported; coupling constants (J) are given in Hz; Ardesignates an aromatic proton when such an assignment is made;

(ix) chemical symbols have their usual meanings; SI units and symbolsare used;

(x) reduced pressures are given as absolute pressures in pascals (Pa);elevated pressures are given as gauge pressures in bars;

(xi) solvent ratios are given in volume:volume (v/v) terms; and

(xii) mass spectra (MS) were run with an electron energy of 70 electronvolts in the chemical ionization (CI) mode using a direct exposureprobe; where indicated ionization was effected by electron impact (EI)or fast atom bombardment (FAB); values for m/z are given; generally,only ions which indicate the parent mass are reported.

Example 1

N-[2-(3,4-Dichlorophenyl)-2-pyrrolidin-1-ylethyl]-benzamidehydrochloride salt.

2-(3,4-Dichlorophenyl)-2-(pyrrolidin-1-yl)ethylamine (2.46 g), benzoylchloride (1.34 g) and triethylamine (1.92 g) were stirred indichloromethane (25 mL) at 23° C., for 48 hours. The reaction was pouredinto water, and the seperated organic layer was dried, and evaporated toa brown oil (2.85 g). Chromatography, with chloroform (1200 mL) and thenmethanol:chloroform (5:95) as the eluent, gave an oil. Trituration ofthe oil with diethylether gave a white solid which was dissolved indichloromethane and treated with hydrochloric acid (g)/diethylether. Thesolution was evaporated to give the title compound as a white glass (330mg); mp 129° C. (after resolidifing); MS: m/z=636(M+1); NMR: 1.78 (m,4),2.54 (m,4), 3.5 (m,2), 4 (m,1), 6.16 (broad s,1), 7.21 (m,1), 7.42(m,5), 7.62 (m,2): Analysis Calculated: C, 55.22; H, 5.49; N, 6.78;Found: C, 55.21; H, 5.24; N, 6.59.

The intermediate 2-(3,4-dichlorophenyl)-2-(pyrrolidin-1-yl)-ethylaminewas prepared as follows.

a) α-Pyrrolidin-1-yl-3,4-dichlorobenzyl cyanide hydrochloride salt.Trimethylsilylcyanide (2.02 g) and catalytic zinc iodide were added to asolution of 3,4-dichlorobenzaldehyde (2.86 g) in dichloromethane (40 mL)at 23° C. The reaction was stirred at 23° C. for 20 minutes and treatedwith a solution of pyrrolidine (1.16 g) in methanol (20 mL). Thereaction was refluxed for 2 hours and stirred 18 hours at 23° C. Thereaction was cooled in an ice bath and treated with hydrochloric acid(g)/methanol (pH=1 to 2). The reaction was stirred at 23° C. for 1 hourand evaporated to a gold oil which was used directly in the nextreaction.

b) 2-(Pyrrolidin-1-yl)-2-(3,4-dichlorophenyl)ethylamine. A slurry ofαPyrrolidin-1-yl-3,4-dichlorobenzyl cyanide hydrochloride salt (4.73 g)in tetrahydrofuran (100 mL) was added to a slurry of lithium aluminumhydride (3.23 g) in tetrahydrofuran (35 mL) while maintaining a reflux.The reaction was allowed to reflux 18 hours. The reaction was cooled inan ice bath and treated with aqueous sodium sulfate. The reaction wasfiltered and evaporated to give a reddish-brown oil. The oil wasdissolved in diethylether, treated with hydrochloric acid(g)/diethylether, and evaporated to a red oil which was used directly insubsequent reactions.

Example 2

N-[2-(3,4-Dichlorophenyl)-2-(4-hydroxy-4-phenyl-piperidino)ethyl]-N-methyl-2-methoxyphenylacetamidehydrochloride salt.

A solution of 2-methoxyphenyl acetic acid (570 mg) and1,1'carbonyldiimidazole (610 mg) in tetrahydrofuran (10 mL) was stirredat reflux for 0.5 hours. The reaction was cooled to 23° C. and treatedwith a solution ofN-[2-(3,4-dichlorophenyl)-2-(4-hydroxy-4-phenylpiperdino)ethyl]methylamine(940 mg) in tetrahydrofuran (50 mL). The reaction was stirred at 23° C.for 18 hours. The reaction was evaporated to a gold oil. The oil wasdissolved in dichloromethane (30 mL), treated with hydrochloric acid(g)/ether, and evaporated to a yellow oil, which was dissolved indichloromethane (10 mL) and added dropwise to diethylether (500 mL). Thetitle compound precipitated as a white solid; mp 205-208° C.; MS:m/z=527(M+1); NMR: 1.75 (m,2), 2.43 (m,1), 2.6 (m,1), 2.81 (s,3), 3.12(m,3), 3.48 (m,4), 3.69 (s,3), 3.76 (m,4), 4.17 (m,1), 4.35 (m,1), 4.79(m,1), 6.67 (d,1), 6.77 (d,1,), 7.31 (m,6), 7.76 (m,2), 8.05 (s,1),11.66 (s,1,) 11.73 (s,1). Analysis Calculated: C, 61.76; H, 5.9; N,4.97; Found: C, 61.68; H, 5.96; N, 4.91.

The intermediateN-[2-(3,4-dichlorophenyl)-2-(4-hydroxy-4-phenylpiperdino)ethyl]methylaminewas prepared as follows.

a) α(4-Hydroxy-4-phenylppiperidino)-3,4-dichlorobenzyl cyanidehydrochloride salt. Trimethylsilylcyanide (2.02 g) and catalytic zinciodide were added to a solution of 3,4-dichlorobenzaldehyde (2.86 g) indichloromethane (45 mL) at 23° C. The reaction was stirred at 23° C. for20 minutes and treated with a solution of 4-hydroxy-4-phenylpiperdine(2.89 g) in methanol (20 mL). The reaction was refluxed for 2.5 hoursand stirred 18 hours at 23° C. The reaction was cooled in an ice bathand treated with hydrochloric acid (g)/ether (pH=1 to 2). The reactionwas stirred at 23° C. for 1 hour and evaporated give to a tan oil.Trituration of the oil with ether:hexane:ethanol (1:1:1) gave the titlecompound as a pale yellow solid (5.09 g) which was used directly insubsequent reactions; MS: m/z=361(M+1).

b) 2-(3,4-Dichlorophenyl)-2-(4-hydroxy-4-phenylpiperdino)-ethylamine. Aslurry of α(4-hydroxy-4-phenylppiperidino)-3,4-dichlorobenzyl cyanidehydrochloride salt (5.09 g) in tetrahydrofuran (50 mL) was added to aslurry of lithium aluminum hydride (2.43 g) in tetrahydrofuran (40 mL)at reflux. After 18 hours, the reaction was cooled in an ice bath,treated with aqueous sodium sulfate, filtered, and dried (NaSO4), togive material which was used directly in subsequent reactions.

c)N-Acetyl-2-(3,4-dichlorophenyl)-2-(4-hydroxy-4-phenylpiper-dino)ethylamine.A mixture of2-(3,4-dichlorophenyl)-2-(4-hydroxy-4-phenylpiperdino)ethylamine (4.68g) in tetrahydrofuran (200 mL), sodium carbonate (1.36 g) andmethylchloroformate (1.21 g) was stirred at 23° C. for 48 hours. Thereaction was evaporated, partitioned between dichloromethane (300 mL)and water (200 mL), and the seperated organic layer was dried andevaporated to give a gold oil, which was used directly in subsequentreactions.

d)N-[2-(3,4-Dichlorophenyl)-2-(4-hydroxy-4-phenylpiperdino)-ethyl]methylamine.N-Acetyl-2-(3,4-dichlorophenyl)-2-(4-hydroxy-4-phenylpiperdino)ethylamine(5.40g) in tetrahydrofuran (50 ml) was added to a slurry of lithium aluminumhydride (1.40 gm, 95%) in tetrahydrofuran while stirring at reflux. Thereaction was allowed to reflux 18 hours, was cooled in an ice bath,treated with an aqueous solution of sodium sulfate, filtered, and dried(Na2SO4), to give material which was used directly in subsequentreactions.

Example 3

N-[2-(3,4-Dichlorophenyl)-2-pyrrolidin-1-ylethyl]-N-methylbenzamidehydrochloride salt.

A solution ofN-[2-(3,4-dichlorophenyl)-2-pyrrolidin-1-yl-ethyl]benzamide (260 mg) indimethylsulfoxide (1.5 mL) and methyl iodide (230 mg) were added to asolution of KOH (190 mg) in dimethylsulfoxide (0.7 mL). The reaction wasstirred at 23° C. for 3/4 hour, was poured into water (10 mL), andextracted with dichloromethane (20 mL). The organic layer was washed(brine), dried and evaporated to a gold oil. Chromatography, with ethylacetate:hexane (50:50 then 75:25) as the eluent, gave an oil, which wasdissolved in diethylether and treated with hydrochloric acid(g)/diethylether to provide the title compound as a white solid (60 mg);mp 199-202° C.; MS: m/z=377(M+1); NMR: 1.98 (m,1), 2.12 (m,2), 2.35(m,1), 2.54 (s,3,), 2.61 (m,1), 3.35 (m,2), 3.88 (t,1), 4.13 (m,1), 4.63(m,2), 7.2 (dd,1), 7.26 (s,1), 7.53 (d,1), 7.79 (broad s,1), 8.11 (broads,1), 13.23 (broad s,1). Analysis Calculated: C, 57.43; H, 5.6; N, 6.7;Found: C, 57.59; H, 5.61; N, 6.35.

Example 4

N-[2-(3,4-Dichlorophenyl)-2-(4-hydroxy-4-phenyl-piperidino)ethyl]benzamidehydrochloride salt.

Benzoyl chloride (290 mg) and triethylamine (420 mg) were added to asolution of2-(3,4-Dichlorophenyl)-2-(4-hydroxy-4-phenyl-piperdino)ethylamine (750mg) in tetrahydrofuran (37.5 mL). The reaction was stirred at 23° C. for18 hours, and was evaporated to an oil-solid mixture. The mixture waspartitioned between water (100 mL) and dichloromethane (100 mL), and theseperated organic layer was dried and evaporated to an off-white solid(1.01 gm). Treatment of a solution of this solid in diethylether withhydrochloric acid (g)/diethylether followed by recrystalization of thehydrochloride salt from ethylacetate (hot,minimum volume) provided thetitle compound as a white solid (450 mg); mp 232-235° C.; MS:m/z=469(M+1); NMR: 1.8 (m,2), 2.44 (m,1), 2.63 (m,1), 3.17 (m,3), 3.99(m,2), 4.27 (m,1), 4.76 (m,1), 5.4 (broad s,1), 7.26 (m,1), 7.46 (m,7),7.8 (m,5), 11.37 (broad s,1). Analysis Calculated: C, 61.73; H, 5.38; N,5.54; Found: C, 61.8; H, 5.5; N, 5.52.

Example 5

N-[2-(3,4-Dichlorophenyl)-2-(4-hydroxy-4-phenyl-piperidino)ethyl]-N-methylbenzamide.

N-[2-(3,4-Dichlorophenyl)-2-(4-hydroxy-4-phenylpiperdino)-ethyl]methylamine(450 mg), benzoyl chloride (168 mg), and triethylamine (120 mg) intetrahydrofuran were stirred at 23° C. for 48 hours. The reaction wasfiltered concentrated to a gold oil. Chromatography, with chloroform andthen methanol:chloroform (5:95) as the eluent, gave a gold oil.Trituration of the oil with diethylether/hexane provided a white solid;MS: m/z=483(M+1); NMR: 1.77 (m,2), 2.4 (m,1), 2.63 (m,1), 2.72 (m,3),3.2 (m,3), 3.83 (m,1), 4.36 (m,2), 4.93 (m,1), 5.43 (broad s,1), 7.03(m,2), 7.41 (m,7), 7.83 (m,2). Analysis Calculated: C, 60.28; H, 5.8; N,5.21; Found: C, 60.25; H, 5.52; N, 5.14.

Example 6

N-[2-3,4-Dichlorophenyl)-2-(4-hydroxy-4-phenylpiperidino)-ethyl]phenylacetamidehydrochloride salt.

Phenyl acetylchloride (330 mg) and triethylamine (420 mg) were added toa solution of2-(3,4-dichlorophenyl)-2-(4-hydroxy-4-phenylpiperdino)ethylamine (750mg) in tetrahydrofuran (38 mL). The reaction was stirred at 23° C. for18 hours, was evaporated to an oil-solid mixture, and was partitionedbetween water (100 mL) and dichloromethane (100 mL). The organic layerwas dried and the filtrate evaporated to a gold oil. The oil wasdissolved in diethylether and treated with hydrochloric acid(g)/diethylether. The ether layer was concentrated to a gold oil. Theoil was partitioned between H20 (300 mL) and diethylether (300 mL). Theaqueous layer was basified (ph=12) with sodium bicarbonate and extractedwith diethylether (2×150 mL). This ether layer was treated withhydrochloric acid (g)/diethylether and concentrated to a gold oil.

Trituration of the oil with diethylether provided the title compound asa tan glass (100 mg); mp 129-133° C.: NMR: 1.77 (m,2), 2.33 (m,2,), 3.13(m,4), 3.81 (m,2), 4.04 (m,1), 4.71 (m,1), 5.39 (broad s,1), 7.02 (m,2),7.33 (m,8), 7.61 (d,1), 7.75 (d,1), 8.1 (s,1), 8.5 (broad s,1), 10.94(broad s,1). Analysis Calculated: C, 60.79; H, 5.76; N, 5.25; Found: C,60.6; H, 5.47; N, 4.96.

Example 7

N-[2-(3,4-Dichlorophenyl)-2-(4-hydroxy-4-phenylpiperidino)ethyl]-N-methylphenylacetamidehydrochloride salt.

N-[2-(3,4-Dichlorophenyl)-2-(4-hydroxy-4-phenylpiperdino)-ethyl]methylamine(450 mg), phenylacetylchloride (190 mg) and triethylamine (120 mg) intetrahydrofuran (25 mL) were stirred at 23° C. for 48 hours. Thereaction was evaporat ed to a gold oil. Chromatography, with chloroformand then methanol:chloroform (5:95) as the eluent, provided a gold oil(420 mg). A solution of this oil in diethylether (15 mL) was treatedwith hydrochloric acid (g)/ether (4 mL) t o give t he title compound asa white solid (200 mg); mp 109 (some melt then resolidifies), 137-139°C.; MS: m/z=497(M+1); NMR: 1.77 (m,2), 2.49 (m,1), 2.65 (m,2), 2.81(broad s,3), 3.05 (m,3), 3.56 (m,3), 4.17 (m,1), 4.32 (m,1), 4.74 (broads,1), 6.96 (broad s,2), 7.33 (m,10), 7.67 (broad s,2), 8 (broad s,1),11.64 (broad s,1). Analysis Calculated: C, 62.99; H, 5.66; N, 5.25;Found: C, 62.69; H, 5.9; N, 5.14.

Example 8

N-[2-(3,4-Dichlorophenyl)-2-(4-hydroxy-4-phenylpiperidino)ethyl]-N-methyl-3,5-bis (trifluoromethyl)phenylacetamide hydrochloridesalt.

A solution of 3,5-bis(trifluoromethyl)phenylacetic acid (1.61 g) and1,1'-carbonyldiimidazole (1.01 g) in tetrahydrofuran (15 mL) was stirredat reflux for 0.5 hours. The reaction was cooled to 23° C. and treatedwith a solution ofN-[2-(3,4-dichlorophenyl)-2-(4-hydroxy-4-phenylpiperdino)ethyl]methylamine(2.24 g) in tetrahydrofuran (70 mL). The reaction was stirred at 23° C.for 18 hours. The reaction was evaporated to an oil, and the oil waspartitioned between diethylether and 1N hydrochloric acid (100 mL). Theorganic layer was treated with etheral hydrochloric acid to produce thetitle compound as a white solid (950 mg); mp 230° C.; MS: m/z=633(M+1);NMR: 1.73 (m,2), 2.42 (m,1), 2.75 (m,1), 3.01 (s,4), 3.86 (m,4,), 4.43(m,1), 4.85 (m,1), 5.34 (m,1), 7.34 (m,5), 7.73 (s2), 7.87 (m,5), 8.06(s,1), 11.36 (broad s,1). Analysis Calculated: C, 53.79; H, 4.36; N,4.18; Found: C, 54.06; H, 4.48; N, 4.23.

Example 9

N-[2-(3,4-Dichlorophenyl)-2-(4-hydroxy-4-phenylpiperidino)ethyl]-N-methyl-3-isopropoxyphenylacetamidehydrochloride salt.

A solution of 3-isopropoxyphenylacetic acid (670 mg) and1,1'carbonyldiimidazole (590 mg) in tetrahydrofuran (15 mL) was stirredat reflux for 0.5 hours. The reaction was cooled to 23° C. and treatedwith a solution ofN-[2-(3,4-dichlorophenyl)-2-(4-hydroxy-4-phenylpiperdino)ethyl]methylamine(940 mg) in tetrahydrofuran (40 mL). The reaction was stirred at 23° C.for 18 hours. The reaction was evaporated to a gold oil. The oil waspartitioned between diethylether (100 mL) and 1 N hydrochloric acid (150mL). The organic layer was treated with hydrochloric acid (g)/ether andevaporated to give a yellow oil which was dissolved in dichloromethane(10 mL) and added dropwise to diethylether (500 mL). The title compoundprecipitated as a white solid (480 mg); mp 127-132° C.; MS:m/z=555(M+1); NMR: 1.23 (d,3), 1.25 (d,3), 1.75 (m,2), 2.4 (m,1), 2.7(m,1), 2.83 (s,3), 3.13 (m,2), 3.43 (m,2), 3.54 (s,2), 3.73 (m,1), 4.52(m,1), 5.37 (m,1), 6.38 (d,1), 6.66 (s,1,), 6.73 (d,1), 7.01 (m,3,),7.22 (m,2,), 7.46 (d,2), 7.7 (s,2,), 8.05 (s,1), 11.73 (s,1). AnalysisCalculated: C, 61.95; H, 6.37; N, 4.66; Found: C, 61.94; H, 6.3; N,4.56.

Example 10

N-[2-(3,4-Dichlorophenyl)-2-(1,4-dioxa-8-azospiro(4.5)decan-8-yl)ethyl]-N-methyl-3-isopropoxyphenylacetamide.

A solution of 2-isopropoxyphenyl acetic acid (109 mg) and1,1'carbonyldiimidazole (91 mg) in ethyl acetate (3 mL) was stirred onceand reacted 1 1/2 hours at 23° C. while under a blanket of nitrogen. Thesolution was treated with a solution ofN-(methyl)-2-(3,4-dichlorophenyl)-2-(1,4-dioxa-8-azospiro(4.5)decan-8-yl)ethylamine(175 mg) in 2.5 mL of ethylacetate, stirred once and allowed to stand 24hours under a blanket of nitrogen. Chromatography on a Varian Mega BondElute Si 1225-6034 column, 60 cc, 10 gm, MFG code 2217 with chloroformas the eluent gave the title compound; MS: m/z=521(M+1), HPLC purity55%, rt=15.175. HPLC purity determined on a SPERISORB column (ODS 5u,purchased from Hewlet Packard, catalogue number 7992402-584) with a flowrate of 1.5 mL/minute, and an oven temp of 40° C., using UV detection(280nm). Two solvent systems were used to determine HPLC purity and theyare designated Solvent A and Solvent B, herein. Solvent A is 1 mmoltriethylamine in water, and Solvent B is 1 mmol triethylamine inacetonitrile. For the title compound, t=0-3 minutes, 95:5(A/B), t=17-20minutes, 5:95(A/B), t=30 minutes 95:5(A/B).

a. α-(1,4-Dioxa-8-azospiro(4.5)decan-8-yl)-3,4-dichlorobenzyl cyanide.3,4-Dichlorobenzaldehyde (2.59 g) in methanol (8 mL) was added to asolution of sodium bisulfite (1.54 g) in water (6 mL) at 23° C. under anitrogen atmosphere. The mixture was cooled to 0-5° C., treated with1,4-dioxa-8-azospiro(4.5)decane (2.12 g), followed by potassium cyanide(965 mg). The mixture was stirred in an ice-water bath and allowed towarm overnight to room temperature. The mixture was filtered and theresulting solid washed with methanol:water (1:1) to give the nitrile asa pale yellow solid, which was dried and used directly in subsequentreactions; MS: m/z=327(M+1); NMR: 1.75 (m,4), 2.65 (t,4), 3.96 (s,4),4.82 (s,1), 7.39 (d,1), 7.42 (d,1), 7.65 (s,1).

b.2-(1,4-Dioxa-8-azospiro(4.5)decan-8-yl)-2-(3,4-dichlorophenyl)ethylamine.Asolution of (a) (11.00 g) in tetrahydrofuran (50 mL) was added to aslurry of lithium aluminum hydride (2.68 g, 95%) in tetrahydrofuran (100mL) while maintaining a reflux while under a nitrogen atmosphere. Thereaction was allowed to reflux for 18 hours. The solution was cooled inan ice bath and treated with aqueous sodium sulfate (saturated). Themixture was filtered, dried (NaSO₄), and the resulting material was useddirectly in subsequent reactions.

c.N-(Methoxycarbonyl)-2-(3,4-dichlorophenyl)-2-(1,4-dioxa-8-azospiro(4.5)decan-8-yl)ethylamine.A mixture of (b) (11.13 g) in tetrahydrofuran (300 mL), sodium carbonate(3.56 g) and methylchloroformate (3.18 g) was stirred at 23° C. for 18hours while under a nitrogen atmosphere. The mixture was concentrated toan orange solid. The solid was partitioned between methylene chloride(200 mL) and water (200 mL). The organic layer was dried andconcentrated under reduced pressure to a gold oil. The oil was usedwithout further purification in subsequent reactions.

d.N-(Methyl)-2-(3,4-dichlorophenyl)-2-(1,4-dioxa-8-azospiro-(4.5)decan-8-yl)ethylamine.A solution of (c) (13.08 g) in tetrahydrofuran (50 mL) was added to aslurry of lithium aluminum hydride (2.61 g, 95%) in tetrahydrofuran (80mL) while stirring at reflux under a nitrogen atmosphere. The solutionwas refluxed 18 hours, cooled in an ice bath and treated with an aqueoussolution of sodium sulfate (saturated). The mixture was filtered, dried(Na₂ SO₄), and used directly in subsequent reactions; MS: m/z=345(M+1).

EXAMPLES 11-23

Using a procedure similar to that described in Example 10 exceptreplacingN-methyl-2-(3,4-dichlorophenyl)-2-(1,4-dioxa-8-azospiro(4.5)decan-8-yl)ethylaminewith N-(methyl)-2-(3,4-dichloro-phenyl)-2-(4-phenylpiperidino)ethylamineand replacing 2-isopropyloxy-phenylacetic acid with the requisitecarboxylic acid, the following compounds of formula I wherein Q¹ is4-phenylpiperidino, Q² is methyl, Q³ is hydrogen, Q⁴ is dichlorophenyl,and Q⁵ has the value defined were prepared.

Example 11

Q⁵ =3,5-Bis(trifluoromethyl)benzyl; MS: m/z=617(M+1); HPLC: solventmethod B, rt=15.946.

Example 12

Q⁵ =3-Isopropoxybenzyl; MS: m/z=539(M+1); HPLC: Solvent B, rt=16.206.

Example 13

Q⁵ =2,4-Diflurobenzyl; MS: m/z=517(M+1); HPLC: Solvent A, rt=18.504.

Example 14

Q⁵ =2-Trifluoromethylbenzyl; MS: m/z=549(M+1); HPLC: Solvent A,rt=19.009.

Example 15

Q⁵ 3-Fluorobenzyl; MS: m/z=499(M+1); HPLC: Solvent A, rt=18.464.

Example 16

Q⁵ =2,5-Difluorobenzyl; MS: m/z=517(M+1); HPLC: Solvent A, rt=18.465.

Example 17

Q⁵ =4-Trifluoromethylbenzyl; MS: m/z=549(M+1); HPLC: Solvent A,rt=15.591.

Example 18

Q⁵ 3,5-Dichlorophenyl; MS: m/z=535,537,539(M+1); HPLC: Solvent A,rt=19.359.

Example 19

Q⁵ =3,5-Dimethylphenyl; MS: m/z=495(M+1); HPLC: Solvent A, rt=19.245.

Example 20

Q⁵ =Benzyl; MS: m/z=481(M+1); HPLC: Solvent B, rt=16.855.

Example 21

Q⁵ =9-Xanthenyl; MS: m/z=571(M+1); HPLC: Solvent B, rt=14.209.

Example 22

Q⁵ =2-Methoxybenzyl; MS: m/z=511(M+1); Solvent A, rt=15.868.

Example 23

Q⁵ =3,5-Dimethoxyphenyl; MS: m/z=527(M+1); Solvent A, rt=18.159.

EXAMPLES 24-36

Using a procedure similar to that described in Example 10 exceptreplacingN-methyl-2-(3,4-dichlorophenyl)-2-(1,4-dioxa-8-azospiro(4.5)decan-8-yl)ethylaminewith2-(3,4-dichlorophenyl)-2-(4-hydroxy-4-phenylpiperidino)-N-(methyl)ethylamineand replacing 2-(isopropyloxy)phenylacetic acid with the requisitecarboxylic acid, the following compounds of formula I wherein Q¹ is4-hydroxy-4-phenyl-piperidino, Q² is methyl, Q³ is hydrogen, Q₄ isdichlorophenyl, and Q⁵ has the value defined were prepared.

Example 24

Q⁵ =3,5-Bis(trifluoromethyl)benzyl; MS: m/z=633(M+1); HPLC: Solvent B,rt=14.059.

Example 25

Q⁵ =3-Isopropoxybenzyl; MS: m/z=555(M+1); HPLC: Solvent B, rt=14.912.

Example 26

Q⁵ 2,4-Diflurobenzyl; MS: m/z=533(M+1); HPLC: Solvent B, rt=14.181.

Example 27

Q⁵ =2-Trifluoromethylbenzyl; MS: m/z=565(M+1); HPLC: Solvent B,rt=14.890.

Example 28

Q⁵ =3-Fluorobenzyl; MS: m/z=515(M+1); HPLC: Solvent B, rt=14.909.

Example 29

Q⁵ =2,5-Difluorobenzyl; MS: m/z=533(M+1); HPLC: Solvent B, rt=14.311.

Example 30

Q⁵ =4-Trifluoromethylbenzyl; MS: m/z=565(M+1); HPLC: Solvent B,rt=15.130.

Example 31

Q⁵ =3,5-Dichlorophenyl; MS: m/z=551,553,555(M+1); HPLC: Solvent B,rt=15.282.

Example 32

Q⁵ =3,5-Dimethylphenyl; MS: m/z=511(M+1); HPLC: Solvent B, rt=15.019.

Example 33

Q⁵ =Benzyl; MS: m/z=497(M+1); HPLC: Solvent B, rt=14.607.

Example 34

Q⁵ =9-Xanthenyl; MS: m/z=587(M+1); HPLC: Solvent B, rt=15.182.

Example 35

Q⁵ =2-Methoxybenzyl; MS: m/z=527(M+1); Solvent B, rt=14.378.

Example 36

Q⁵ =3,5-Dimethoxyphenyl; MS: m/z=543(M+1); Solvent B, rt=14.266.

EXAMPLES 37-49

Using a procedure similar to that described in Example 10 exceptreplacingN-methyl-2-(3,4-dichlorophenyl)-2-(1,4-dioxa-8-azospiro(4.5)decan-8-yl)ethylaminewith 2-(3,4-dichlorophenyl)-2-(4-benzylpiperidino)-N-(methyl)ethylamineand replacing 2-(isopropyloxy)phenylacetic acid with the requisitecarboxylic acid, the following compounds of formula I wherein Q¹ is4-benzylpiperidino, Q² is methyl, Q³ is hydrogen, Q⁴ is dichlorophenyl,and Q⁵ has the value defined were prepared.

Example 37

Q⁵ =3,5-Bis(trifluoromethyl)benzyl; MS: m/z=631(M+1); HPLC: Solvent B,rt=18.7725.

Example 38

Q⁵ =3-Isopropoxybenzyl; MS: m/z=553(M+1); HPLC: Solvent B, rt=18.945.

Example 39

Q⁵ =2,4-Diflurobenzyl; MS: m/z=531(M+1); HPLC: Solvent A, rt=19.325.

Example 40

Q⁵ =2-Trifluoromethylbenzyl; MS: m/z=563(M+1); HPLC: Solvent B,rt=19.195.

Example 41

Q⁵ =3-Fluorobenzyl; MS: m/z=513(M+1); HPLC: Solvent B, rt=17.276.

Example 42

Q⁵ =2,5-Difluorobenzyl; MS: m/z=531(M+1); HPLC: Solvent rt=18.663.

Example 43

Q⁵ =4-Trifluoromethylbenzyl; MS: m/z=563(M+1); HPLC: Solvent B,rt=18.955.

Example 44

Q⁵ =3,5-Dichlorophenyl; MS: m/z=549,551,553(M+1); HPLC: Solvent B,rt=19.570.

Example 45

Q⁵ =3,5-Dimethylphenyl; MS: m/z=509(M+1); HPLC: Solvent B, rt=19.092.

Example 46

Q⁵ =Benzyl; MS: m/z=495(M+1); HPLC: Solvent B, rt=18.592.

Example 47

Q⁵ =9-Xanthenyl; MS: m/z=585(M+1); HPLC: Solvent B, rt=19.309.

Example 48

Q⁵ =2-Methoxybenzyl; MS: m/z=525(M+1); Solvent B, rt=18.559.

Example 49

Q⁵ =3,5-Dimethoxyphenyl; MS: m/z=541(M+1); Solvent B, rt=16.781.

EXAMPLES 50-58

Using a procedure similar to that described in Example 10 exceptreplacing 2-(isopropyloxy)phenylacetic acid with the requisitecarboxylic acid, the following compounds of formula I wherein Q¹ is1,4-dioxa-8-azospiro(4.5)decan-8-yl, Q² is methyl, Q³ is hydrogen, Q⁴ isdichlorophenyl, and Q⁵ has the value defined were prepared.

Example 50

Q⁵ =3-Isopropoxybenzyl; MS: m/z=521(M+1); HPLC: Solvent B, rt=15.175.

Example 51

Q⁵ =2,4-Diflurobenzyl; MS: m/z=499(M+1); HPLC: Solvent B, rt=15.505.

Example 52

Q⁵ =3-Fluorobenzyl; MS: m/z=481(M+1); HPLC: Solvent B, rt=15.278.

Example 53

Q⁵ =2,5-Difluorobenzyl; MS: m/z=499(M+1); HPLC: Solvent B, rt=15.225.

Example 54

Q⁵ =4-Trifluoromethylbenzyl; MS: m/z=531(M+1); HPLC: Solvent B,rt=15.805.

Example 55

Q⁵ =3,5-Dimethylphenyl; MS: m/z=477(M+1); HPLC: Solvent B, rt=15.660.

Example 56

Q⁵ =9-Xanthenyl; MS: m/z=553(M+1); HPLC: Solvent B, rt=15.575.

Example 57

Q⁵ =2-Methoxybenzyl; MS: m/z=493(M+1); Solvent B, rt=15.766.

Example 58

Q⁵ =3,5-Dimethoxyphenyl; MS: m/z=509(M+1); Solvent B, rt=14.459.

EXAMPLES 59-129

Using a procedure similar to that outlined in Scheme II and described indetail below, the following compounds of formula XI wherein Q⁵ has theindicated value were prepared from2-(3,4-dichlorophenyl)-2-(4-hydroxy-4-phynylpiperidino)-N-(methyl)ethylamine and the requisite carboxylic acid of formula X.

A solution of carbonyl diimide (0.3 mmol) in ethyl acetate (2 mL) wasadded to the requsite acid (0.3 mmol) and the mixture was stirred for50° C. for 30 minutes. A solution of2-(3,4-dichlorophenyl)-2-(4-hydroxy-4-phenylpiperidino)-N-(methyl)ethylamine(0.3 mmol) in ethyl acetate (5 mL) was added and the reaction tube wasshaken and then stirred at 50° C. for 12 hours. The tube was allowed tocool for 30 minutes and the resulting solution was filtered. Thesolution was washed with saturated aqueous sodium bicarbonate (5 mL) andwater (5 mL). The solvent was removed under vacuum over 2 hours.Chromatography gave the compounds of formula I, which were analysed forpurity using HPLC.

For starting acids which were in the form of hydrochloride salts, anadditional equivalent of triethylamine was added before addition ofcarbonyl diimidazole. For acids which were hydrates, an additionalequivalent of carbonyl diimidazole was added.

High performance liquid chromatography was performed on a HYPERSIL ODS5u column (purchased from Hewlet Packard, catalog number 7992402-584),at an oven temperature of 40° C. using Ultraviolet detection, at awavelength of 280 nm. Chromatography was carried out at a flow rate of1.5 mL/minute using the following gradient solvent system.

    ______________________________________                                        Time           Solvent C                                                                              Solvent D                                               (minutes) (%) (%)                                                           ______________________________________                                        0-17           95       5                                                       17-18 5 95                                                                    18-20 95 5                                                                  ______________________________________                                         Solvent C triethylamine (1 mM) in water.                                      Solvent D triethylamine (1 mM) in acetonitrile.                          

Example 59

Q⁵ =3,5-bis(trifluoromethyl)benzyl; rt=13.95.

Example 60

Q⁵ =4-nitrobenzoyl; rt=12.7.

Example 61

Q⁵ =9-fluorenyl; rt=13.89.

Example 62

Q⁵ =3-adamantyl; rt=15.5.

Example 63

Q⁵ =3,5-dimethylphenyl; rt=15.93.

Example 64

Q⁵ =5-fluoro-3-indolyl; rt=12.64.

Example 65

Q⁵ =2-naphthyl; rt=9.98.

Example 66

Q⁵ =2-naphthyloxy; rt=13.52.

Example 67

Q⁵ =β-methoxystyryl; rt=15.35.

Example 68

Q⁵ =4-(4-methylphenylsulfonylamino)phenyl; rt=1.5.

Example 69

Q⁵ =4-fluorobenzyl; rt=12.53.

Example 70

Q⁵ =2-(ethoxy)ethyl; rt=12.22.

Example 71

Q⁵ =methyl; rt=11.7.

Example 72

Q⁵ =cyanomethyl; rt=11.57.

Example 73

Q⁵ =methoxymethyl; rt=11.6.

Example 74

Q⁵ =3,4,5-trimethoxystyryl; rt=12.41.

Example 75

Q⁵ =4-(ethoxycarbonyl)butyl; rt=12.49.

Example 76

Q⁵ =a radical of formula XII; rt=11.59.

Example 77

Q⁵ =5-nitrofuran-2-yl; rt=12.39.

Example 78

Q⁵ =5-oxo-4,5-dihydro-pyrazol-3-yl (a radical of formula XIII);rt=11.65.

Example 79

Q⁵ =2-thienyl; rt=12.61.

Example 80

Q⁵ =5-methoxyindol-2-yl; rt=12.76.

Example 81

Q⁵ =pyrid-1-ylmethyl; rt=11.6.

Example 82

Q⁵ =hydantoin-5-ylmethyl; rt=11.71.

Example 83

Q⁵ =2-methyl-3-furyl; rt=12.42.

Example 84

Q⁵ =a radical of formula XXIII; rt=9.95.

Example 85

Q⁵ =4-phenoxyphenyl; rt=13.84.

Example 86

Q⁵ =3,4-methylenedioxyphenyl; rt=12.66.

Example 87

Q⁵ =1-benzyloxycarbonylamino-5-(tertbutoxycarbonylamino)-pentanyl;rt=13.96.

Example 88

Q⁵ =2-norbornanylmethyl; rt=13.17.

Example 89

Q⁵ =trifluoromethyl; rt=12.93.

Example 90

Q⁵ =2-pyrazinyl; rt=11.83.

Example 91

Q⁵ =3-pyridyl; rt=11.83.

Example 92

Q⁵ =phthalimidomethyl; rt=12.43.

Example 93

Q⁵ =3-fluorophenyl; rt=12.41.

Example 94

Q⁵ =2,4-dihydroxypyrimidin-5-yl; rt=9.7.

Example 95

Q⁵ =3-(tretbutoxycarbonylamino)propyl; rt=12.51.

Example 96

Q⁵ =3-pyridylmethyl; rt=11.88.

Example 97

Q⁵ =4-pyridyl; rt=11.85.

Example 98

Q⁵ =a radical of formula XVII; rt=10.7.

Example 99

Q⁵ =formyl; rt=11.35.

Example 100

Q⁵ =3-(N,N-dimethylamino)propyl; rt=11.88.

Example 101

Q⁵ =4-fluoro-3-nitrophenyl; rt=12.07.

Example 102

Q⁵ =4-pyridylmethyl; rt=11.84.

Example 103

Q⁵ =styrylsulfonylmethyl; rt=12.58.

Example 104

Q⁵ =2-nitro-3,4-dihydroxyphenyl; rt=1.62.

Example 105

Q⁵ =fluoroacetyl; rt=11.82.

Example 106

Q⁵ =(2-(formylamino)imidazol-4-yl)(methoxyimino)methyl; rt=12.63.

Example 107

Q⁵ =1-acetylimino-2-imidazol-4-ylethyl; rt=10.98.

Example 108

Q⁵ =1-acetylpiperidin-4-yl; rt=11.64.

Example 109

Q⁵ =4-(N,N-dimethylamino)benzyl; rt=13.12.

Example 110

Q⁵ =1-naphthylmethyl; rt=13.65.

Example 111

Q⁵ =3,5-di(benzyloxy)phenyl; rt=15.39.

Example 112

Q⁵ =5-(5-methyl-2-thioxoimidazolidin-4-yl)pentyl; rt=11.79.

Example 113

Q⁵ =α-(formylamino)-α-(methyl)benzyl; rt=12.32.

Example 114

Q⁵ =1,2,3,4-tetrahydroacridin-9-yl (a radical of formula XIX); rt=11.85.

Example 115

Q⁵ =2-(4-methylbenzyloxy)-1-(tertbutoxycarbonylamino)-ethyl; rt=13.35.

Example 116

Q⁵ =2-benzo[b]furan-2-yl; rt=13.12.

Example 117

Q⁵ =5,6-dimethylbenzimidazol-1-ylmethyl; rt=13.15.

Example 118

Q⁵ =1,2,3-triazol-4-yl; rt=11.82.

Example 119

Q⁵ =3,4-dichlorobenzyl; rt=13.6.

Example 120

Q⁵ =4-fluorophenoxymethyl; rt=12.62

Example 121

Q⁵ =a radical of formula XXIV; rt=11.77.

Example 122

Q⁵ =1-(benzyloxycarbonylaminoacetyl)pyrrolidin-3-yl; rt=13.57.

Example 123

Q⁵ =perfluorophenyl; rt=13.55.

Example 124

Q⁵ =tert-butoxycarbonylaminomethyl; rt=12.53.

Example 125

Q⁵ =3,3,3-trifluoropropyl; rt=12.7.

Example 126

Q⁵ =4-imidazolidinyl; rt=11.76.

Example 127

Q⁵ =5-cyclohexylpentyl; rt=16.5.

Example 128

Q⁵ =2-oxoimidazolidin-1-ylmethyl; rt=11.74.

Example 129

Q⁵ =5-benzoylpentyl; rt=13.25. ##STR2##

What is claimed is:
 1. A compound of formula I, wherein:p is the integer0 or 1; R^(bb) is an aromatic or heteroaromatic group; R^(bc) ishydrogen, hydroxy, (C₁ -C₄)alkoxy, (C₁ -C₄)alkanoyloxy, COOR^(bd),cyano, NR^(be) R^(bf) or SR^(bg) ; R^(bd) is hydrogen or (C₁ -C₃)alkyl;R^(be) and R^(bf) are independently hydrogen, (C₁ -C₄)alkyl, (C_(1-C)₄)hydroxyalkyl or (C₁ -C₄)alkanoyl; and R^(bg) is hydrogen or (C₁-C₄)alkyl; Q² is hydrogen or (C₁ -C₃)alkyl; Q⁴ is phenyl, which may bearone or two substituents independently selected from halo,trifluoromethyl, hydroxy, (C₁ -C₃)alkoxy and (C₁ -C₃)alkyl; or Q⁴ isthienyl, imidazolyl, benzo[β]thiophenyl or naphthyl, any of which maybear a halo substituent; or Q⁴ is biphenylyl; or Q⁴ is carbon-linkedindolyl, which may bear a benzyl substituent at the 1-position; and Q⁵is formyl, 4-imidazolidinyl, 3-pyrrolidinyl (wherein the nitrogen issubstituted by hydrogen, (C₁ -C₃)alkyl, acyl, orbenzyloxycarbonylaminoacetyl), (C₃ -C₆)cycloalkyl, trifluoromethyl,4-piperidino (wherein the nitrogen is substituted by hydrogen, (C₁-C₃)alkyl, or acyl), aryl, heteroaryl, pyrid-1-ylmethyl, fluorenyl,β-styryl, a radical of formula XII-XXII: ##STR3## or xanthenyl; or Q⁵ is(C₁ -C₈)alkyl which may be substituted by 0-3 substituents selected fromaryl, heteroaryl, (aryl)oxy, aryl(C₁ -C₃)-alkyl, heteroaryl(C₁-C₃)alkyl, (C₁ -C₆)alkyl, (heteroaryl)oxy, benzyloxy, (C₃-C₆)cycloalkyl, adamantyl, norbornanyl, β-styryl, cyano,trifluoromethyl, oxo, hydroxy, (C₁ -C₄)alkoxy, --NR^(a) R^(b),--NC(═O)NR^(c) R^(d), --NC(═O)OR^(e), --C(═O)OR^(f), --S(O)R^(g),--S(O)₂ R^(h), ═NR^(i), SR^(j), and the radicals of formulae XII-XXII;R^(a) -R^(b) are independently selected from hydrogen, acyl, formyl, and(C₁ -C₄)alkyl, or the group NR^(a) R^(b) may form a cyclic groupselected from pyrrolidino, piperidino, morpholino, thiomorpholino (orits S-oxide) or piperazinyl (which piperazinyl may bear a (C₁ -C₃)alkylsubstituent at the 4-position); R^(c) -R^(f) and R^(j) are independentlyselected from hydrogen, phenyl, benzyl, phenethyl and (C₁ --C₄)alkyl;R^(g) and R^(h) are independently selected from hydrogen, phenyl,benzyl, phenethyl, β-styryl and (C₁ -C₄)alkyl; R^(i) is hydrogen, (C₁-C₄)alkyl, acyl or (C₁ -C₄)alkoxy; wherein any aryl or heteroaryl in, orany aryl or heteroaryl portion of, Q⁵, or any aryl or heteroaryl portionof R^(a) -R^(j), may be unsubstituted or may bear 1-5 substituentsselected from halo, cyano, trifluoromethyl, (C₁ -C₄)alkyl, (C₁-C₄)alkoxy, methylenedioxy, phenoxy, benzyloxy, NR^(k) R^(m), --NS(O)₂aryl (wherein the aryl group may be substituted by 0-3 (C₁ -C₃)alkylgroups), hydroxy, --SR^(n), and nitro; and wherein any β-styryl may besubstituted at the β-position by a (C₁ -C₃)alkoxy; R^(k) -R^(m) areindependently selected from hydrogen, acyl, formyl, and (C₁ -C₄)alkyl,or the group NR^(k) R^(m) may form a cyclic group selected frompyrrolidino, piperidino, morpholino, thiomorpholino (or its S-oxide) orpiperazinyl (which piperazinyl may bear a (C₁ -C₃)alkyl substituent atthe 4-position); and R^(n) is hydrogen or (C₁ -C₃)alkyl; or the N-oxideof a piperidino nitrogen in Q¹ indicated by Δ in formula I; or apharmaceutically acceptable salt thereof; or a quaternary ammonium saltthereof in which the piperidino nitrogen in Q¹ indicated by Δ in formulaI is a quadricovalent ammonium nitrogen wherein the fourth radical onthe nitrogen, R¹, is (C₁ -C₄)alkyl or benzyl and the associatedcounterion, A, is a pharmaceutically acceptable anion.
 2. A compound asclaimed in claim 1 wherein Q⁵ is formyl, 4-imidazolidinyl,3-pyrrolidinyl (wherein the nitrogen is substituted by hydrogen, (C₁-C₃)alkyl, acyl, or benzyloxycarbonylaminoacetyl), (C₃ -C₆)cycloalkyl,trifluoromethyl, 4-piperidino (wherein the nitrogen is substituted byhydrogen, (C₁ -C₃)alkyl, and acyl), aryl, heteroaryl pyrid-1-ylmethyl,fluorenyl, β-styryl, a radical of formula XII-XXII or xanthenyl; or Q⁵is (C₁ -C₆)alkyl which may be substituted by one substituent selectedfrom aryl, heteroaryl, (aryl)oxy, (heteroaryl)oxy, benzyloxy, (C₃-C₆)cycloalkyl, adamantyl, norbornanyl, β-styryl, cyano,trifluoromethyl, oxo, hydroxy, (C₁ -C₄)alkoxy, --NR^(a) R^(b),--NC(═O)NR^(c) R^(d), --NC(═O)OR^(e), --C(═O)OR^(f), --S(O)R^(g),--S(O)₂ R^(h), ═NR^(i), SR^(j), and the radicals of formulae XII-XXII.3. A compound as claimed in claim 1, wherein:Q⁵ is aryl, or heteroaryl;or Q⁵ is a radical of formula III: ##STR4## wherein: a) R¹ is aryl,heteroaryl, aryl(C₁ -C₃)alkyl or heteroaryl(C₁ -C₃)alkyl; and R² and R³are independently hydrogen, aryl, heteroaryl, aryl(C₁ -C₃)alkyl,heteroaryl(C₁ -C₃)alkyl, (C₁ -C₆)alkyl or (C₃ -C₆)cycloalkyl; or b) R¹and R² together with the carbon to which they are attached form a (C₃-C₆)cycloalkyl and R³ is hydrogen or (C₁ -C₆)alkyl; wherein any aryl orheteroaryl ring in Q⁵ may be unsubstituted or may bear one or moresubstituents selected from halo, cyano, trifluoromethyl, (C₁ -C₄)alkyl,(C₁ -C₄)alkoxy, methylenedioxy, hydroxy and nitro.
 4. A compound asclaimed in claim 1 wherein:R^(bb) is phenyl; R^(bc) is hydrogen,hydroxyl or acetamido; Q² is methyl, ethyl or propyl; Q⁴ is3,4-dichlorophenyl or 3,4-methylenedioxyphenyl; and Q⁵ is selected fromthe group consisting of phenyl, benzyl, 2-methoxyphenyl,3,5-bis(trifluoromethyl)benzyl, 2-isopropoxybenzyl,3,5-bis(trifluoromethyl)phenyl, 2-methoxybenzyl, 3,5-dimethylphenyl,3,5-dimethylbenzyl, 3,5-dichlorophenyl, 3,5-dichlorobenzyl,3,5-dimethoxyphenyl, and 3,5-dimethoxybenzyl.
 5. A compound as claimedin claim 4 wherein:p is 0; R^(bb) is phenyl; R^(bc) is hydrogen orhydroxyl; Q⁵ is phenyl, benzyl, 2-methoxyphenyl, 2-methoxybenzyl,3,5-bis(trifluoromethyl)phenyl, 3,5-bis(trifluoromethyl)benzyl,3,5-dimethylphenyl, 3,5-dimethylbenzyl, 3,5-dichlorophenyl,3,5-dichlorobenzyl, 3,5-dimethoxyphenyl, or 3,5-dimethoxybenzyl.
 6. Acompound as claimed in claim 5 wherein R^(bc) is hydrogen.
 7. A compoundas claimed in claim 5 wherein R^(bc) is hydroxyl.
 8. A compound asclaimed in claim 5 wherein:Q⁵ is phenyl, benzyl, 2-methoxyphenyl,3,5-bis(trifluoromethyl)benzyl or 3,5-bis(trifluoromethyl)phenyl.
 9. Apharmaceutical composition comprising a compound of formula I as definedin claim
 1. 10. A method of treating substance P or neurokinin A relatedpathology in rheumatoid arthritis, Alzheimer's disease, oedema, allergicrhinitis, inflammation pain, gastrointestinal hypermotility, irritablebowel syndrome, anxiety, emesis, Huntington's Disease, psychoses,hypertension, migraine, urinary incontinence, bladder hypermotility andurticaria in a human or other mammal in need thereof, comprisingadministering a NK1 or NK2 receptor antagonistic effective amount of acompound of claim
 1. 11. A method of treating symptoms cause by neuronalstimulation of airway epithelium in a human or other mammal in needthereof, comprising administering NK1 or NK2 receptor antagonisticeffective amount of a compound of claim
 1. 12. The method of claim 11wherein said symptoms are in asthma.